rs1136688

Variant names:

• chr6-29942984-G-A
• rs1136688
• NM_002116.8:c.301G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-29942984-G-A
• chr6-29942984-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):​c.301G>A​(p.Asp101Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D101G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (2166 hom., cov: 5)
  • Exomes 𝑓: 0.41 (111284 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.38
• Publications: 28 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089042485).

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.301G>A	p.Asp101Asn	missense	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.301G>A	p.Asp101Asn	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.301G>A	p.Asp101Asn	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.301G>A	p.Asp101Asn	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.232 AC: 10636 AN: 45876 Hom.: 2156 Cov.: 5

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.373 AC: 84634 AN: 227064 AF XY: 0.379

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.404

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.407 AC: 357115 AN: 876508 Hom.: 111284 Cov.: 20 AF XY: 0.407 AC XY: 177341 AN XY: 435366

African (AFR) AF: 0.357 AC: 7446 AN: 20834

American (AMR) AF: 0.361 AC: 8299 AN: 22980

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 7696 AN: 14980

East Asian (EAS) AF: 0.151 AC: 1881 AN: 12438

South Asian (SAS) AF: 0.400 AC: 22872 AN: 57158

European-Finnish (FIN) AF: 0.195 AC: 6467 AN: 33228

Middle Eastern (MID) AF: 0.453 AC: 1339 AN: 2956

European-Non Finnish (NFE) AF: 0.423 AC: 286364 AN: 676796

Other (OTH) AF: 0.420 AC: 14751 AN: 35138

GnomAD4 genome AF: 0.232 AC: 10660 AN: 45888 Hom.: 2166 Cov.: 5 AF XY: 0.219 AC XY: 4956 AN XY: 22658

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

African (AFR) AF: 0.302 AC: 3191 AN: 10572

American (AMR) AF: 0.266 AC: 842 AN: 3168

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 253 AN: 870

East Asian (EAS) AF: 0.0558 AC: 86 AN: 1540

South Asian (SAS) AF: 0.234 AC: 340 AN: 1456

European-Finnish (FIN) AF: 0.0730 AC: 334 AN: 4576

Middle Eastern (MID) AF: 0.329 AC: 25 AN: 76

European-Non Finnish (NFE) AF: 0.236 AC: 5374 AN: 22736

Other (OTH) AF: 0.266 AC: 153 AN: 576

⚠️ 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: 0.383 Hom.: 2716

ESP6500AA AF: 0.268 AC: 1178

ESP6500EA AF: 0.314 AC: 2688

ExAC AF: 0.351 AC: 41456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.79
DEOGEN2	Benign	0.022	T
Eigen	Benign	-2.9
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.015	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.94	T
PhyloP100		-4.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.013
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.081
ClinPred		0.0021	T
GERP RS		-7.2
PromoterAI		-0.0046	Neutral
Varity_R		0.27
gMVP		0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1136688; hg19: chr6-29910761; COSMIC: COSV65136637;