6-31271601-T-C

Variant names:

• chr6-31271601-T-C
• rs1131123
• NM_002117.6:c.341A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002117.6(HLA-C):​c.341A>G​(p.Asp114Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 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: not found (cov: 7)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: HLA-C NM_002117.6 missense, splice_region
• Scores: Splicing: ADA: 0.00008525
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 33 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]

ENSG00000288813 (HGNC:):

ACMG classification

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=0.07640898).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	NM_002117.6	MANE Select	c.341A>G	p.Asp114Gly	missense splice_region	Exon 2 of 8	NP_002108.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.341A>G	p.Asp114Gly	missense splice_region	Exon 2 of 8	ENSP00000365402.5
	HLA-C	ENST00000383329.7	TSL:6	c.341A>G	p.Asp114Gly	missense splice_region	Exon 2 of 8	ENSP00000372819.3
	HLA-C	ENST00000415537.1	TSL:6	c.338A>G	p.Asp113Gly	missense splice_region	Exon 2 of 5	ENSP00000400410.1

Frequencies

GnomAD3 genomes Cov.: 7

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084206 Hom.: 0 Cov.: 30 AF XY: 0.00000184 AC XY: 1 AN XY: 542078

⚠️ 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: 23908

American (AMR) AF: 0.00 AC: 0 AN: 32408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20962

East Asian (EAS) AF: 0.00 AC: 0 AN: 26212

South Asian (SAS) AF: 0.00 AC: 0 AN: 72760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3810

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 823814

Other (OTH) AF: 0.00 AC: 0 AN: 45150

⚠️ 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 Cov.: 7

Alfa AF: 0.00 Hom.: 6240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.015	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.20
Sift	Benign	0.45	T
Sift4G	Benign	0.53	T
Polyphen		0.0030	B
Vest4		0.052
MutPred		0.38		Loss of stability (P = 0.0457)
MVP		0.10
MPC		0.74
ClinPred		0.063	T
GERP RS		-1.9
PromoterAI		-0.017	Neutral
gMVP		0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.020		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: rs1131123; hg19: chr6-31239378;