6-29943321-T-C

Variant names:

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.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. 13/20 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).

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0490

Publications

14 publications found

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:

POLR1HASP (HGNC:):

POLR1HASP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

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.397T>C	p.Phe133Leu	missense	Exon 3 of 8	NP_002107.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.397T>C	p.Phe133Leu	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
HLA-A	ENST00000952344.1		c.397T>C	p.Phe133Leu	missense	Exon 3 of 8	ENSP00000622403.1
HLA-A	ENST00000706894.1		c.397T>C	p.Phe133Leu	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes

AF:

0.0318

AC:

1864

AN:

58698

Hom.:

181

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0368

AC:

8680

AN:

235726

AF XY:

0.0374

show subpopulations

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 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.:

AF XY:

0.0114

AC XY:

4822

AN XY:

423974

show subpopulations

African (AFR)

AF:

0.0375

AC:

774

AN:

20632

American (AMR)

AF:

0.0146

AC:

351

AN:

24008

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

195

AN:

13932

East Asian (EAS)

AF:

0.00236

AC:

AN:

16108

South Asian (SAS)

AF:

0.0192

AC:

1163

AN:

60618

European-Finnish (FIN)

AF:

0.0112

AC:

359

AN:

32164

Middle Eastern (MID)

AF:

0.0175

AC:

AN:

2740

European-Non Finnish (NFE)

AF:

0.00886

AC:

5641

AN:

636576

Other (OTH)

AF:

0.0145

AC:

504

AN:

34868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

297

594

892

1189

1486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0319

AC:

1875

AN:

58760

Hom.:

183

Cov.:

AF XY:

0.0309

AC XY:

879

AN XY:

28406

show subpopulations

African (AFR)

AF:

0.0611

AC:

1084

AN:

17750

American (AMR)

AF:

0.0230

AC:

103

AN:

4486

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

AN:

1148

East Asian (EAS)

AF:

0.00173

AC:

AN:

1154

South Asian (SAS)

AF:

0.0247

AC:

AN:

1296

European-Finnish (FIN)

AF:

0.0106

AC:

AN:

4906

Middle Eastern (MID)

AF:

0.00909

AC:

AN:

110

European-Non Finnish (NFE)

AF:

0.0205

AC:

549

AN:

26842

Other (OTH)

AF:

0.0216

AC:

AN:

742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0236

Hom.:

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.0

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.021

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.94

PhyloP100

-0.049

PrimateAI

Benign

0.31

PROVEAN

Benign

1.9

REVEL

Benign

0.046

Sift

Benign

0.41

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.029

MutPred

0.19

Loss of loop (P = 0.0986)

MPC

0.097

ClinPred

0.041

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over