rs1131123

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002117.6(HLA-C):c.341A>T(p.Asp114Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,143,468 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 7)

Exomes 𝑓: 0.0000037 ( 1 hom. )

Consequence

HLA-C
NM_002117.6 missense, splice_region

Scores

Splicing: ADA: 0.0002117

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.18

Publications

33 publications found

Variant links:

Genes affected

HLA-C (HGNC:4933): (major histocompatibility complex, class I, C) HLA-C belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. About 6000 HLA-C alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

HLA-C links:

ENSG00000288813 (HGNC:):

ENSG00000288813 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10472956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.341A>T	p.Asp114Val	missense_variant, splice_region_variant	Exon 2 of 8	ENST00000376228.10	NP_002108.4	P10321-1Q6R739Q95HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10 link	c.341A>T	p.Asp114Val	missense_variant, splice_region_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.0000169

AC:

AN:

59272

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:

0.0000316

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249686

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1084196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

542072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23908

American (AMR)

AF:

0.00

AC:

AN:

32408

Ashkenazi Jewish (ASJ)

AF:

0.0000477

AC:

AN:

20962

East Asian (EAS)

AF:

0.00

AC:

AN:

26212

South Asian (SAS)

AF:

0.00

AC:

AN:

72758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3810

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

823808

Other (OTH)

AF:

0.00

AC:

AN:

45150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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:

0.0000169

AC:

AN:

59272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28066

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

12512

American (AMR)

AF:

0.00

AC:

AN:

5270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1530

East Asian (EAS)

AF:

0.00

AC:

AN:

1490

South Asian (SAS)

AF:

0.00

AC:

AN:

1834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.0000316

AC:

AN:

31642

Other (OTH)

AF:

0.00

AC:

AN:

728

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

6240

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.023

T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.95

PhyloP100

-1.2

PrimateAI

Benign

0.22

PROVEAN

Benign

0.98

N;N

REVEL

Benign

0.20

Sift

Benign

0.12

T;T

Sift4G

Uncertain

0.018

D;D

Polyphen

0.0070

B;B

Vest4

0.14

MutPred

0.40

Gain of MoRF binding (P = 0.0423);Gain of MoRF binding (P = 0.0423);

MVP

0.15

MPC

0.80

ClinPred

0.15

GERP RS

-1.9

PromoterAI

0.018

Neutral

(source)

gMVP

0.41

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: 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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over