6-31271601-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002117.6(HLA-C):​c.341A>C​(p.Asp114Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,085,990 control chromosomes in the GnomAD database, including 45,795 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.11 (845 hom., cov: 7)
  • Exomes 𝑓: 0.15 (44950 hom.)
• Consequence: HLA-C NM_002117.6 missense, splice_region
• Scores: Splicing: ADA: 0.00007417
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7902476E-5).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

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>C	p.Asp114Ala	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>C	p.Asp114Ala	missense splice_region	Exon 2 of 8	ENSP00000365402.5
	HLA-C	ENST00000383329.7	TSL:6	c.341A>C	p.Asp114Ala	missense splice_region	Exon 2 of 8	ENSP00000372819.3
	HLA-C	ENST00000415537.1	TSL:6	c.338A>C	p.Asp113Ala	missense splice_region	Exon 2 of 5	ENSP00000400410.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 6206 AN: 55690 Hom.: 844 Cov.: 7

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.0442

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0698

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.513 AC: 128111 AN: 249686 AF XY: 0.512

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.155 AC: 159443 AN: 1030260 Hom.: 44950 Cov.: 30 AF XY: 0.165 AC XY: 84724 AN XY: 514634

African (AFR) AF: 0.159 AC: 3474 AN: 21912

American (AMR) AF: 0.229 AC: 6859 AN: 29968

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 8756 AN: 20006

East Asian (EAS) AF: 0.516 AC: 12390 AN: 24010

South Asian (SAS) AF: 0.321 AC: 21836 AN: 68034

European-Finnish (FIN) AF: 0.192 AC: 6262 AN: 32580

Middle Eastern (MID) AF: 0.317 AC: 1138 AN: 3588

European-Non Finnish (NFE) AF: 0.115 AC: 90746 AN: 787738

Other (OTH) AF: 0.188 AC: 7982 AN: 42424

GnomAD4 genome AF: 0.111 AC: 6208 AN: 55730 Hom.: 845 Cov.: 7 AF XY: 0.111 AC XY: 2933 AN XY: 26492

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

African (AFR) AF: 0.0759 AC: 895 AN: 11790

American (AMR) AF: 0.112 AC: 554 AN: 4944

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 612 AN: 1478

East Asian (EAS) AF: 0.189 AC: 254 AN: 1342

South Asian (SAS) AF: 0.182 AC: 319 AN: 1754

European-Finnish (FIN) AF: 0.0698 AC: 245 AN: 3512

Middle Eastern (MID) AF: 0.115 AC: 14 AN: 122

European-Non Finnish (NFE) AF: 0.108 AC: 3201 AN: 29666

Other (OTH) AF: 0.140 AC: 94 AN: 670

⚠️ 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: 0.445 Hom.: 6240

TwinsUK AF: 0.480 AC: 1778

ALSPAC AF: 0.478 AC: 1842

ExAC AF: 0.513 AC: 62192

Asia WGS AF: 0.546 AC: 1896 AN: 3476

EpiCase AF: 0.468

EpiControl AF: 0.483

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.45
DANN	Benign	0.71
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.0080	T
MetaRNN	Benign	0.000018	T
MetaSVM	Benign	-0.91	T
PhyloP100		-1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	4.0	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.62
ClinPred		0.0011	T
GERP RS		-1.9
PromoterAI		0.040	Neutral
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.0		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; COSMIC: COSV66110096; COSMIC: COSV66110096;