6-31271845-C-A

Position:

chr6-31271845-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002117.6(HLA-C):c.97G>T(p.Asp33Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D33F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.094 ( 480 hom., cov: 6)

Exomes 𝑓: 0.31 ( 126868 hom. )

Failed GnomAD Quality Control

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -20.0

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.3951443E-6).

BP6

Variant 6-31271845-C-A is Benign according to our data. Variant chr6-31271845-C-A is described in ClinVar as [Benign]. Clinvar id is 1246876.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-C	NM_002117.6 linkuse as main transcript	c.97G>T	p.Asp33Tyr	missense_variant	2/8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10 linkuse as main transcript	c.97G>T	p.Asp33Tyr	missense_variant	2/8		NM_002117.6	ENSP00000365402	P4	P10321-1

Frequencies

GnomAD3 genomes

AF:

0.0943

AC:

4763

AN:

50508

Hom.:

480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0915

Gnomad AMI

AF:

0.0665

Gnomad AMR

AF:

0.0854

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0577

Gnomad MID

AF:

0.144

Gnomad NFE

AF:

0.0866

Gnomad OTH

AF:

0.0973

GnomAD3 exomes

AF:

0.634

AC:

135031

AN:

212864

Hom.:

45559

AF XY:

0.632

AC XY:

73187

AN XY:

115814

show subpopulations

Gnomad AFR exome

AF:

0.663

Gnomad AMR exome

AF:

0.698

Gnomad ASJ exome

AF:

0.761

Gnomad EAS exome

AF:

0.765

Gnomad SAS exome

AF:

0.635

Gnomad FIN exome

AF:

0.638

Gnomad NFE exome

AF:

0.575

Gnomad OTH exome

AF:

0.642

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.306

AC:

281666

AN:

920940

Hom.:

126868

Cov.:

AF XY:

0.317

AC XY:

145749

AN XY:

460376

show subpopulations

Gnomad4 AFR exome

AF:

0.396

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.628

Gnomad4 EAS exome

AF:

0.712

Gnomad4 SAS exome

AF:

0.519

Gnomad4 FIN exome

AF:

0.344

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.313

GnomAD4 genome

AF:

0.0942

AC:

4763

AN:

50552

Hom.:

480

Cov.:

AF XY:

0.0902

AC XY:

2195

AN XY:

24340

show subpopulations

Gnomad4 AFR

AF:

0.0914

Gnomad4 AMR

AF:

0.0855

Gnomad4 ASJ

AF:

0.344

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.144

Gnomad4 FIN

AF:

0.0577

Gnomad4 NFE

AF:

0.0866

Gnomad4 OTH

AF:

0.0949

Alfa

AF:

0.458

Hom.:

2718

ESP6500AA

AF:

0.582

AC:

1718

ESP6500EA

AF:

0.533

AC:

2852

ExAC

AF:

0.566

AC:

67538

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

This variant is associated with the following publications: (PMID: 30476138) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0010

DANN

Benign

0.51

DEOGEN2

Benign

0.020

T;.

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.9

FATHMM_MKL

Benign

0.00035

LIST_S2

Benign

0.0043

T;T

MetaRNN

Benign

0.0000024

T;T

MetaSVM

Benign

-0.76

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

2.2

N;N

REVEL

Uncertain

0.29

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.032

B;B

Vest4

0.027

MPC

0.68

ClinPred

0.011

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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