chr6-31269347-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002117.6(HLA-C):​c.1087A>T​(p.Thr363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0 (0 hom., cov: 4)
  • Exomes 𝑓: 0.0000015 (0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09292412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.1087A>T	p.Thr363Ser	missense_variant	Exon 7 of 8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.1087A>T	p.Thr363Ser	missense_variant	Exon 7 of 8	6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 46420 Hom.: 0 Cov.: 4

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000148 AC: 1 AN: 676498 Hom.: 0 Cov.: 15 AF XY: 0.00000297 AC XY: 1 AN XY: 337072

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

African (AFR) AF: 0.00 AC: 0 AN: 12276

American (AMR) AF: 0.00 AC: 0 AN: 18282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7686

East Asian (EAS) AF: 0.00 AC: 0 AN: 14998

South Asian (SAS) AF: 0.0000274 AC: 1 AN: 36510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1936

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 532130

Other (OTH) AF: 0.00 AC: 0 AN: 27248

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 46420 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 21922

African (AFR) AF: 0.00 AC: 0 AN: 8776

American (AMR) AF: 0.00 AC: 0 AN: 4056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 608

East Asian (EAS) AF: 0.00 AC: 0 AN: 1186

South Asian (SAS) AF: 0.00 AC: 0 AN: 1176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26244

Other (OTH) AF: 0.00 AC: 0 AN: 530

Alfa AF: 0.00 Hom.: 85300

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.5
DANN	Benign	0.20
DEOGEN2	Benign	0.0013	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.61	T;D;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		-1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.19	N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;D;.
Sift4G	Benign	0.45	T;T;.
Polyphen		0.0080	B;B;.
Vest4		0.091
MutPred		0.29		.;Gain of phosphorylation at T369 (P = 0.0714);.;
MVP		0.29
MPC		0.48
ClinPred		0.070	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.055
Mutation Taster		=100/0	polymorphism

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;