6-29942863-C-T

Variant names:

• chr6-29942863-C-T
• rs3173429
• NM_002116.8:c.180C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002116.8(HLA-A):​c.180C>T​(p.Phe60Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,499,998 control chromosomes in the GnomAD database, including 5,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.065 (754 hom., cov: 17)
  • Exomes 𝑓: 0.044 (4938 hom.)
• Consequence: HLA-A NM_002116.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 11 publications found

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A 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 the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, 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. More than 6000 HLA-A 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]

ENSG00000227766 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=0.339 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. 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-A	NM_002116.8	MANE Select	c.180C>T	p.Phe60Phe	synonymous	Exon 2 of 8	NP_002107.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.180C>T	p.Phe60Phe	synonymous	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.180C>T	p.Phe60Phe	synonymous	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.180C>T	p.Phe60Phe	synonymous	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 7342 AN: 113684 Hom.: 750 Cov.: 17

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.0515

Gnomad EAS AF: 0.00931

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.0397

Gnomad NFE AF: 0.0577

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0599 AC: 14987 AN: 250200 AF XY: 0.0602

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0700

GnomAD4 exome AF: 0.0439 AC: 60787 AN: 1386216 Hom.: 4938 Cov.: 61 AF XY: 0.0442 AC XY: 30479 AN XY: 689992

African (AFR) AF: 0.0854 AC: 2760 AN: 32316

American (AMR) AF: 0.0383 AC: 1613 AN: 42070

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 928 AN: 24242

East Asian (EAS) AF: 0.00389 AC: 143 AN: 36788

South Asian (SAS) AF: 0.0408 AC: 3478 AN: 85294

European-Finnish (FIN) AF: 0.0452 AC: 2245 AN: 49678

Middle Eastern (MID) AF: 0.0620 AC: 309 AN: 4982

European-Non Finnish (NFE) AF: 0.0442 AC: 46596 AN: 1053926

Other (OTH) AF: 0.0477 AC: 2715 AN: 56920

GnomAD4 genome AF: 0.0647 AC: 7357 AN: 113782 Hom.: 754 Cov.: 17 AF XY: 0.0642 AC XY: 3530 AN XY: 54984

African (AFR) AF: 0.0914 AC: 2905 AN: 31800

American (AMR) AF: 0.0589 AC: 593 AN: 10074

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 136 AN: 2640

East Asian (EAS) AF: 0.00934 AC: 36 AN: 3856

South Asian (SAS) AF: 0.0424 AC: 165 AN: 3888

European-Finnish (FIN) AF: 0.0509 AC: 385 AN: 7562

Middle Eastern (MID) AF: 0.0427 AC: 10 AN: 234

European-Non Finnish (NFE) AF: 0.0577 AC: 2977 AN: 51568

Other (OTH) AF: 0.0610 AC: 92 AN: 1508

Alfa AF: 0.0549 Hom.: 80

EpiCase AF: 0.0738

EpiControl AF: 0.0785

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
PhyloP100		0.34
PromoterAI		-0.13	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs3173429; hg19: chr6-29910640; COSMIC: COSV65140273;