6-31269347-T-C

Variant names:

• chr6-31269347-T-C
• rs1130838
• NM_002117.6:c.1087A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002117.6(HLA-C):​c.1087A>G​(p.Thr363Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (470 hom., cov: 4)
  • Exomes 𝑓: 0.092 (25967 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 48 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.327648E-6).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002117.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	NM_002117.6	MANE Select	c.1087A>G	p.Thr363Ala	missense	Exon 7 of 8	NP_002108.4	P10321-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.1087A>G	p.Thr363Ala	missense	Exon 7 of 8	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.1105A>G	p.Thr369Ala	missense	Exon 7 of 8	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.1087A>G	p.Thr363Ala	missense	Exon 7 of 8	ENSP00000626214.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 4149 AN: 39446 Hom.: 464 Cov.: 4

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0781

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.286

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.731 AC: 181760 AN: 248666 AF XY: 0.731

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.873

Gnomad EAS exome AF: 0.802

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.739

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0923 AC: 56322 AN: 609992 Hom.: 25967 Cov.: 15 AF XY: 0.0988 AC XY: 30018 AN XY: 303926

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

African (AFR) AF: 0.311 AC: 3249 AN: 10446

American (AMR) AF: 0.206 AC: 3369 AN: 16378

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 2467 AN: 6720

East Asian (EAS) AF: 0.434 AC: 5769 AN: 13284

South Asian (SAS) AF: 0.222 AC: 7203 AN: 32446

European-Finnish (FIN) AF: 0.133 AC: 3038 AN: 22814

Middle Eastern (MID) AF: 0.246 AC: 415 AN: 1688

European-Non Finnish (NFE) AF: 0.0577 AC: 27816 AN: 482134

Other (OTH) AF: 0.124 AC: 2996 AN: 24082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.105 AC: 4164 AN: 39512 Hom.: 470 Cov.: 4 AF XY: 0.101 AC XY: 1889 AN XY: 18698

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

African (AFR) AF: 0.140 AC: 1050 AN: 7504

American (AMR) AF: 0.114 AC: 385 AN: 3364

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 81 AN: 506

East Asian (EAS) AF: 0.166 AC: 151 AN: 910

South Asian (SAS) AF: 0.129 AC: 131 AN: 1012

European-Finnish (FIN) AF: 0.137 AC: 384 AN: 2812

Middle Eastern (MID) AF: 0.294 AC: 20 AN: 68

European-Non Finnish (NFE) AF: 0.0831 AC: 1875 AN: 22572

Other (OTH) AF: 0.140 AC: 62 AN: 444

⚠️ 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.

Alfa AF: 0.700 Hom.: 85300

TwinsUK AF: 0.656 AC: 2431

ALSPAC AF: 0.654 AC: 2520

ESP6500AA AF: 0.793 AC: 2396

ESP6500EA AF: 0.687 AC: 3724

ExAC AF: 0.731 AC: 88627

Asia WGS AF: 0.766 AC: 2667 AN: 3478

EpiCase AF: 0.686

EpiControl AF: 0.705

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.20
DANN	Benign	0.20
DEOGEN2	Benign	0.00059	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0000083	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.48
ClinPred		0.00019	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.067
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1130838; hg19: chr6-31237124; COSMIC: COSV66117127; COSMIC: COSV66117127;