chr6-29943321-T-C

Position:

• chr6-29943321-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):​c.397T>C​(p.Phe133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 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.

• Frequency:
  • Genomes: 𝑓 0.032 (183 hom., cov: 7)
  • Exomes 𝑓: 0.011 (1014 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034287572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.397T>C	p.Phe133Leu	missense_variant	3/8	ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1460A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.397T>C	p.Phe133Leu	missense_variant	3/8		NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1864 AN: 58698 Hom.: 181 Cov.: 7 FAILED QC

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.0368

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0209

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0218

GnomAD3 exomes AF: 0.0368 AC: 8680 AN: 235726 Hom.: 630 AF XY: 0.0374 AC XY: 4823 AN XY: 128976

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00603

Gnomad SAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0390

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0108 AC: 9073 AN: 841646 Hom.: 1014 Cov.: 13 AF XY: 0.0114 AC XY: 4822 AN XY: 423974

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00236

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00886

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0319 AC: 1875 AN: 58760 Hom.: 183 Cov.: 7 AF XY: 0.0309 AC XY: 879 AN XY: 28406

Gnomad4 AFR AF: 0.0611

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0209

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0216

Alfa AF: 0.0227 Hom.: 37

ESP6500AA AF: 0.0697 AC: 209

ESP6500EA AF: 0.0421 AC: 227

ExAC AF: 0.0394 AC: 4708

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.0
DANN	Benign	0.90
DEOGEN2	Benign	0.021	T;T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.20	.;T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.9	N;N;N;N;.
REVEL	Benign	0.046
Sift	Benign	0.41	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0	B;D;B;B;.
Vest4		0.029
MutPred		0.19		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);
MPC		0.097
ClinPred		0.041	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.11

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: rs1059488; hg19: chr6-29911098;