chr6-31356754-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005514.8(HLA-B):c.277G>A(p.Ala93Thr) 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 (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. A93A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 5437 hom., cov: 5)

Exomes 𝑓: 0.66 ( 264581 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.32

Publications

30 publications found

Variant links:

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B 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. 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, exon 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. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

HLA-B links:

ENSG00000271581 (HGNC:):

ENSG00000271581 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.3709429E-6).

BP6

Variant 6-31356754-C-T is Benign according to our data. Variant chr6-31356754-C-T is described in ClinVar as Benign. ClinVar VariationId is 3061033.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.277G>A	p.Ala93Thr	missense_variant	Exon 2 of 8	ENST00000412585.7	NP_005505.2	P01889E5FQ95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7 link	c.277G>A	p.Ala93Thr	missense_variant	Exon 2 of 8	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

15957

AN:

36896

Hom.:

5432

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.636

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.825

Gnomad EAS

AF:

0.521

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.426

Gnomad MID

AF:

0.733

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.471

GnomAD2 exomes

AF:

0.766

AC:

149551

AN:

195270

AF XY:

0.768

show subpopulations

Gnomad AFR exome

AF:

0.655

Gnomad AMR exome

AF:

0.898

Gnomad ASJ exome

AF:

0.874

Gnomad EAS exome

AF:

0.720

Gnomad FIN exome

AF:

0.738

Gnomad NFE exome

AF:

0.720

Gnomad OTH exome

AF:

0.766

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.662

AC:

600088

AN:

907044

Hom.:

264581

Cov.:

AF XY:

0.666

AC XY:

300379

AN XY:

450786

show subpopulations

African (AFR)

AF:

0.512

AC:

8673

AN:

16950

American (AMR)

AF:

0.858

AC:

25983

AN:

30292

Ashkenazi Jewish (ASJ)

AF:

0.873

AC:

15544

AN:

17812

East Asian (EAS)

AF:

0.635

AC:

12951

AN:

20410

South Asian (SAS)

AF:

0.785

AC:

40902

AN:

52124

European-Finnish (FIN)

AF:

0.588

AC:

16847

AN:

28658

Middle Eastern (MID)

AF:

0.778

AC:

1946

AN:

2502

European-Non Finnish (NFE)

AF:

0.645

AC:

452382

AN:

701698

Other (OTH)

AF:

0.679

AC:

24860

AN:

36598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

4204

8408

12611

16815

21019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10322

20644

30966

41288

51610

<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

AF:

0.433

AC:

15979

AN:

36942

Hom.:

5437

Cov.:

AF XY:

0.426

AC XY:

7462

AN XY:

17512

show subpopulations

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

African (AFR)

AF:

0.285

AC:

2549

AN:

8954

American (AMR)

AF:

0.598

AC:

2024

AN:

3386

Ashkenazi Jewish (ASJ)

AF:

0.825

AC:

1043

AN:

1264

East Asian (EAS)

AF:

0.521

AC:

537

AN:

1030

South Asian (SAS)

AF:

0.470

AC:

280

AN:

596

European-Finnish (FIN)

AF:

0.426

AC:

1024

AN:

2404

Middle Eastern (MID)

AF:

0.741

AC:

AN:

European-Non Finnish (NFE)

AF:

0.438

AC:

8155

AN:

18626

Other (OTH)

AF:

0.467

AC:

201

AN:

430

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.331

Heterozygous variant carriers

323

646

968

1291

1614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.641

Hom.:

3628

ESP6500AA

AF:

0.632

AC:

2616

ESP6500EA

AF:

0.656

AC:

5337

ExAC

AF:

0.694

AC:

82387

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HLA-B-related disorder

Benign:1

Dec 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.0

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.020

T;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.045

T;T;T

MetaRNN

Benign

0.0000024

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-3.3

PROVEAN

Benign

-0.44

N;.;N

REVEL

Benign

0.29

Sift

Benign

0.52

T;.;T

Sift4G

Benign

0.37

T;.;T

Polyphen

0.0

B;.;.

Vest4

0.047

MPC

0.22

ClinPred

0.00033

GERP RS

-2.7

PromoterAI

-0.16

Neutral

(source)

Varity_R

0.066

gMVP

0.047

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over