rs397514477

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_031448.6(C19orf12):c.-2C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: -0.906

Publications

24 publications found

Variant links:

Genes affected

C19orf12 (HGNC:25443): (chromosome 19 open reading frame 12) This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

C19orf12 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 4
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Illumina, Ambry Genetics, G2P
hereditary spastic paraplegia 43
Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

C19orf12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 19-29708415-G-A is Pathogenic according to our data. Variant chr19-29708415-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C19orf12	NM_031448.6 link	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	ENST00000323670.14	NP_113636.2	Q9NSK7-4
C19orf12	NM_031448.6 link	c.-2C>T		5_prime_UTR_variant	Exon 2 of 3	ENST00000323670.14	NP_113636.2	Q9NSK7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 link	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4
C19orf12	ENST00000323670.14 link	c.-2C>T		5_prime_UTR_variant	Exon 2 of 3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249206

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000394

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4

Pathogenic:7Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Founder variant in Turkish population (Olgiati et al 2017); Mean age of onset is 25 yrs in persons homozygous for this variant (Hartig et al 2013). -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients (PMID:22584950,23278385,21981780,25592411,23166001,23436634). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21981780,23436634). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23278385,28347615). -

Aug 06, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr11Met variant in C19orf12 has been identified in at least 13 individuals (9 consanguinous homozygous individuals and 2 compound heterozygous individuals) with neurodegeneration with brain iron accumulation (NBIA) and segregated with disease in at least 5 affected members of 4 families (Hartig 2001 PMID 21981780, Schulte 2013 PMID 23436634, Gore 2016 PMID 27801611, Olgiati 2017 PMID 28347615, Alavi 2020 PMID 31970231). It has also been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 31156) and was identified in 0.004% (1/24194) African chromosomes and 0.001% (1/128668) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant falls in noncoding regions of the most abundantly expressed C19orf12 transcripts and functional studies assessing its impact are not available. Additionally, computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive NBIA. ACMG/AMP Criteria applied: PP1_Strong, PM3, PM2_Supporting, BP4. -

Sep 01, 2024

Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is classified as pathogenic based on the following evidence: It has been observed in multiple unrelated patients (PS4-Moderate, PMID: 22584950, 23278385, 21981780, 25592411, 23166001, 23436634), and its allele frequency is below 0.05 (PM2), indicating rarity in population databases. The missense variant represents a common mechanism of disease (PP2). Additionally, it has been previously classified as pathogenic in ClinVar, and the patient’s clinical history is consistent with the disease (PP5). Together, this evidence supports the pathogenic classification. -

Oct 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C19orf12 c.32C>T (p.Thr11Met) variant, which has been described as one of the most common variants associated with mitochondrial membrane protein-associated neurodegeneration, has been identified in a homozygous state in nine individuals and in a compound heterozygous state in three individuals (Hartig et al. 2011; Deschauer et al. 2012; Dezfouli et al. 2012; Dogu et al. 2013; Tschentscher et al. 2015). The variant was absent from 750 control chromosomes (Hartig et al. 2011) and has not been reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. It has been suggested that the variant may be associated with a later age of onset since it affects only the longer isoform of the protein (Tschentscher et al. 2015). Based on the evidence, the variant is classified as pathogenic for mitochondrial membrane protein-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The T11M variant in the C19orf12 gene has been reported in the homozygous or compound heterozygousstate in multiple individuals with neurodegeneration with brain iron accumulation (Hartig et al., 2011;Schulte et al., 2013). Several individuals with a homozygous T11M variant exhibited early adulthood onsetof dystonia, spasticity, progressive dementia, and psychiatric disorders, including one individual with aParkinson-like phenotype (Tschentscher et al., 2015). The T11M substitution was not observed inapproximately 6100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The T11M variant isa non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Another missense variant in a nearbyresidue (D18G) has also been reported in the Human Gene Mutation Database in association withneurodegeneration with brain iron accumulation (Stenson et al., 2014), supporting the functional importanceof this region of the protein. We interpret T11M as a pathogenic variant. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Jul 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: C19orf12 c.-2C>T (commonly known as c.32C>T, p.Thr11Met in the literature) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 8e-06 in 249206 control chromosomes (gnomAD). c.-2C>T has been reported in the literature in multiple individuals including homozygous individuals of Turkish origin, affected with neurodegeneration with brain iron accumulation (examples: Tschentscher_2015, Sparber_2021, Dogu_2013). In several families the variant segregated with the disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25592411, 33607528, 23278385). ClinVar contains an entry for this variant (Variation ID: 31156). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary spastic paraplegia 43

Pathogenic:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 11 of the C19orf12 protein (p.Thr11Met). This variant is present in population databases (rs397514477, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation (PMID: 21981780, 23278385, 23436634, 25592411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31156). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4

Pathogenic:1

Jan 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormality of iron homeostasis

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

0.0078

BayesDel_noAF

Benign

-0.14

CADD

Benign

2.8

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0076

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.55

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.34

PhyloP100

-0.91

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.56

Sift

Benign

0.10

Sift4G

Benign

0.11

Vest4

0.72

MVP

0.96

MPC

0.53

ClinPred

0.68

GERP RS

-12

PromoterAI

0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.43

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over