Variant 6-29943309-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002116.8(HLA-A):c.385T>C(p.Ser129Pro) 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.17 ( 1947 hom., cov: 6)

Exomes 𝑓: 0.26 ( 54455 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.424

Variant links:

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]

HLA-A links:

LOC124901298 (HGNC:):

LOC124901298 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011473894).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.385T>C	p.Ser129Pro	missense_variant	3/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1472A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.385T>C	p.Ser129Pro	missense_variant	3/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

8580

AN:

50086

Hom.:

1945

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.516

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.0635

Gnomad MID

AF:

0.240

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.157

GnomAD3 exomes

AF:

0.318

AC:

72655

AN:

228474

Hom.:

14458

AF XY:

0.329

AC XY:

41253

AN XY:

125212

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.183

Gnomad ASJ exome

AF:

0.429

Gnomad EAS exome

AF:

0.360

Gnomad SAS exome

AF:

0.415

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.346

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.258

AC:

160584

AN:

621420

Hom.:

54455

Cov.:

AF XY:

0.275

AC XY:

86942

AN XY:

316392

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.187

Gnomad4 ASJ exome

AF:

0.357

Gnomad4 EAS exome

AF:

0.474

Gnomad4 SAS exome

AF:

0.463

Gnomad4 FIN exome

AF:

0.124

Gnomad4 NFE exome

AF:

0.243

Gnomad4 OTH exome

AF:

0.277

GnomAD4 genome

AF:

0.171

AC:

8584

AN:

50122

Hom.:

1947

Cov.:

AF XY:

0.163

AC XY:

3940

AN XY:

24180

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.212

Gnomad4 EAS

AF:

0.516

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.0635

Gnomad4 NFE

AF:

0.211

Gnomad4 OTH

AF:

0.156

Alfa

AF:

0.330

Hom.:

2820

ESP6500AA

AF:

0.268

AC:

803

ESP6500EA

AF:

0.348

AC:

1878

ExAC

AF:

0.311

AC:

36954

Asia WGS

AF:

0.313

AC:

1091

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.7

DANN

Benign

0.88

DEOGEN2

Benign

0.020

T;T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.0072

.;T;T;T;T

MetaRNN

Benign

0.0011

T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

4.9

N;N;N;N;.

REVEL

Benign

0.042

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.038

MPC

0.10

ClinPred

0.00030

GERP RS

-0.46

Varity_R

0.25

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over