19-29702966-C-T

Position:

chr19-29702966-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_031448.6(C19orf12):c.172G>A(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.26

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity CS012_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_031448.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

PP5

Variant 19-29702966-C-T is Pathogenic according to our data. Variant chr19-29702966-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C19orf12	NM_031448.6 linkuse as main transcript	c.172G>A	p.Gly58Arg	missense_variant	3/3	ENST00000323670.14	NP_113636.2	Q9NSK7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 linkuse as main transcript	c.172G>A	p.Gly58Arg	missense_variant	3/3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000241

AC:

AN:

249134

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000538

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000445

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2018	The p.Gly69Arg in C19orf12 has been reported in the homozygous or compound heter ozygous state in 6 individuals with mitochondrial membrane protein-associated ne urodegeneration (MPAN; Hartig 2011, Hogarth 2013, Goldman 2013, Tschentscher 201 5). It has also been identified in 7/124358 of European chromosomes by gnomAD (h ttp://gnomad.broadinstitute.org); however, this frequency is low enough to be co nsistent with a recessive carrier frequency. This variant has been reported in C linVar (Variation ID 183298). In vitro functional studies support an impact to p rotein function (Landoure 2013) and computational prediction tools and conservat ion analysis are consistent with 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 MPA N. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PS3_Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Aziz Sancar Institute of Experimental Medicine, Istanbul University	Aug 08, 2018	The c.205G>A; p.Gly69Arg (NM_001031726.3) variant is associated with neurodegeneration with brain iron accumulation (Hartig 2011). Our patient had slowly progressive spastic paraparesis without extrapyramidal signs. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 07, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 07, 2021	ACMG classification criteria: PS4 moderate, PM2, PM3, PP3 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	C19orf12: PM3:Very Strong, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2019	- -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

Variant summary: C19orf12 c.172G>A (p.Gly58Arg), also referred to as c.205G>A (p.Gly69Arg), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249134 control chromosomes (gnomAD). c.172G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (e.g. Hartig_2011, Hogarth_2013, Tschentscher_2015). These data indicate that the variant is very likely to be associated with disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary spastic paraplegia 43

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects C19orf12 function (PMID: 23857908). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 31157). This missense change has been observed in individual(s) with neurodegeneration with brain iron accumulation (NBIA) (PMID: 21981780, 23269600, 23494994, 25592411, 30088953). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs515726205, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 69 of the C19orf12 protein (p.Gly69Arg). -

Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;.;.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;.;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

2.9

.;.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Pathogenic

-7.0

.;D;.;D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

.;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Vest4

0.94

MutPred

0.58

Gain of methylation at G58 (P = 0.0172);Gain of methylation at G58 (P = 0.0172);Gain of methylation at G58 (P = 0.0172);.;Gain of methylation at G58 (P = 0.0172);

MVP

0.73

MPC

1.1

ClinPred

0.97

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.86

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over