19-29702977-C-G

Position:

chr19-29702977-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_031448.6(C19orf12):c.161G>C(p.Gly54Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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 Likely_pathogenic. Variant got 7 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 chr19-29702977-C-A is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C19orf12	NM_031448.6 linkuse as main transcript	c.161G>C	p.Gly54Ala	missense_variant, splice_region_variant	3/3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 linkuse as main transcript	c.161G>C	p.Gly54Ala	missense_variant, splice_region_variant	3/3	2	NM_031448.6	ENSP00000313332	P1	Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

249090

Hom.:

AF XY:

0.0000964

AC XY:

AN XY:

134842

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000898

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000131

AC:

192

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000223

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 07, 2023

Variant summary: C19orf12 c.161G>C (p.Gly54Ala) 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. c.161G>C affects the first base pair of Exon 3 and could affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 249090 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation (7.2e-05 vs 0.0006), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.161G>C in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. Two other variants affecting the same base pair have been associated with pathogenicity in ClinVar (c.161G>A (p.Gly54Glu) and c.161G>T (p.Gly54Val)), however enough evidence is not available at this time to determine role of this variant in disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia 43

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 65 of the C19orf12 protein (p.Gly65Ala). This variant is present in population databases (rs752450983, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with C19orf12-related conditions. ClinVar contains an entry for this variant (Variation ID: 1195848). 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 disruptive. This variant disrupts the p.Gly65 amino acid residue in C19orf12. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21981780, 23269600, 31087512). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;.;T;T

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.3

.;.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Pathogenic

-5.4

.;D;.;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D;.;D;.

Sift4G

Uncertain

0.010

D;D;D;D;.

Vest4

0.83

MVP

0.69

MPC

1.2

ClinPred

0.89

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.92

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.12

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