rs1136690

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002116.8(HLA-A):c.311C>A(p.Thr104Asn) 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 (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T104I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 2)

Exomes 𝑓: 0.000019 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.44

Publications

11 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:

ENSG00000227766 (HGNC:):

ENSG00000227766 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07496083).

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.311C>A	p.Thr104Asn	missense	Exon 2 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.311C>A	p.Thr104Asn	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
HLA-A	ENST00000952344.1		c.311C>A	p.Thr104Asn	missense	Exon 2 of 8	ENSP00000622403.1
HLA-A	ENST00000706894.1		c.311C>A	p.Thr104Asn	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

44866

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000455

AC:

AN:

219584

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000989

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

751972

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

371260

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

17836

American (AMR)

AF:

0.000673

AC:

AN:

16334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11402

East Asian (EAS)

AF:

0.00

AC:

AN:

10592

South Asian (SAS)

AF:

0.00

AC:

AN:

43284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2266

European-Non Finnish (NFE)

AF:

0.00000508

AC:

AN:

590720

Other (OTH)

AF:

0.00

AC:

AN:

29714

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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: AC0;AS_VQSR

AF:

0.00

AC:

AN:

44866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22056

African (AFR)

AF:

0.00

AC:

AN:

9600

American (AMR)

AF:

0.00

AC:

AN:

3036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

844

East Asian (EAS)

AF:

0.00

AC:

AN:

1428

South Asian (SAS)

AF:

0.00

AC:

AN:

1290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

23068

Other (OTH)

AF:

0.00

AC:

AN:

550

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.2

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.037

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0086

LIST_S2

Benign

0.018

M_CAP

Benign

0.0015

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.90

PhyloP100

-4.4

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Benign

0.039

Sift

Benign

0.26

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.13

MutPred

0.31

Gain of sheet (P = 0.0125)

MVP

0.061

MPC

0.096

ClinPred

0.050

GERP RS

-7.1

PromoterAI

0.0089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over