6-29943337-G-A

Position:

• chr6-29943337-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_002116.8(HLA-A):​c.413G>A​(p.Arg138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.094 (625 hom., cov: 6)
  • Exomes 𝑓: 0.065 (17440 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -9.93

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]

LOC124901298 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.413G>A	p.Arg138Gln	missense_variant	3/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1444C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.413G>A	p.Arg138Gln	missense_variant	3/8		NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.0935 AC: 4247 AN: 45410 Hom.: 621 Cov.: 6

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0652

Gnomad AMR AF: 0.0975

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.0634

Gnomad OTH AF: 0.0785

GnomAD3 exomes AF: 0.577 AC: 117957 AN: 204520 Hom.: 38163 AF XY: 0.571 AC XY: 63688 AN XY: 111592

Gnomad AFR exome AF: 0.601

Gnomad AMR exome AF: 0.675

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.674

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.564

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0655 AC: 54969 AN: 839698 Hom.: 17440 Cov.: 18 AF XY: 0.0726 AC XY: 30390 AN XY: 418858

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.0547

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0846

GnomAD4 genome AF: 0.0937 AC: 4261 AN: 45454 Hom.: 625 Cov.: 6 AF XY: 0.0922 AC XY: 2022 AN XY: 21930

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0985

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0634

Gnomad4 OTH AF: 0.0794

Alfa AF: 0.502 Hom.: 3816

ESP6500AA AF: 0.579 AC: 1722

ESP6500EA AF: 0.463 AC: 2497

ExAC AF: 0.535 AC: 63404

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.0
DANN	Benign	0.84
DEOGEN2	Benign	0.025	T;T;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0027	N
MetaRNN	Benign	0.000074	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.37	N;N;N;N;.
REVEL	Benign	0.047
Sift	Benign	0.33	T;T;T;.;.
Sift4G	Benign	0.31	T;T;T;T;.
Polyphen		0.0020	B;P;B;B;.
Vest4		0.064
MPC		0.095
ClinPred		0.0087	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3173420; hg19: chr6-29911114; COSMIC: COSV65137272; COSMIC: COSV65137272;