6-29942984-G-A

Position:

• chr6-29942984-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002116.8(HLA-A):​c.301G>A​(p.Asp101Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 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. 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089042485).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.301G>A	p.Asp101Asn	missense_variant	2/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1797C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.301G>A	p.Asp101Asn	missense_variant	2/8		NM_002116.8	P3
	ENST00000429656.1	n.84C>T		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.373 AC: 84634 AN: 227064 Hom.: 16360 AF XY: 0.379 AC XY: 46793 AN XY: 123314

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 SAS exome AF: 0.432

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

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.423

Gnomad4 OTH exome AF: 0.420

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

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.266

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0558

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.0730

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.266

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 v4.3

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;T;T;T;.
Eigen	Benign	-2.9
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.0022	N
MetaRNN	Benign	0.0089	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.1	N;N;N;N;.
REVEL	Benign	0.013
Sift	Benign	0.77	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.045
MPC		0.081
ClinPred		0.0021	T
GERP RS		-7.2
Varity_R		0.27
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs1136688; hg19: chr6-29910761; COSMIC: COSV65136637;