rs397514477

chr19-29708415-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_031448.6(C19orf12):c.-2C>T variant causes a 5 prime UTR 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: -0.906

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-29708415-G-A is Pathogenic according to our data. Variant chr19-29708415-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.-2C>T		5_prime_UTR_variant	2/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14	c.-2C>T		5_prime_UTR_variant	2/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249206 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135206

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 SAS 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: 20 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4 Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	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). -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2015	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. -

Hereditary spastic paraplegia 43 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

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 is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -

Abnormality of iron homeostasis Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	2.8
Dann	Benign	0.89
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.56
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Vest4		0.72
MVP		0.96
MPC		0.53
ClinPred		0.68	D
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs397514477; hg19: chr19-30199322; COSMIC: COSV60365136;