dbSNP rs1050683: HLA-B:p.Ala182Thr (chr6-31356242-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005514.8(HLA-B):c.544G>A(p.Ala182Thr) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 6)

Exomes 𝑓: 0.0038 ( 62 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.587

Publications

13 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:

ENSG00000298396 (HGNC:):

ENSG00000298396 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=0.0057958066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.544G>A	p.Ala182Thr	missense_variant	Exon 3 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7 link	c.544G>A	p.Ala182Thr	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2

Frequencies

GnomAD3 genomes

AF:

0.000462

AC:

AN:

51966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000355

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000707

Gnomad ASJ

AF:

0.00175

Gnomad EAS

AF:

0.000488

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000540

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00595

AC:

1397

AN:

234822

AF XY:

0.00513

show subpopulations

Gnomad AFR exome

AF:

0.00189

Gnomad AMR exome

AF:

0.0224

Gnomad ASJ exome

AF:

0.00990

Gnomad EAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.000479

Gnomad NFE exome

AF:

0.00206

Gnomad OTH exome

AF:

0.00825

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00376

AC:

4612

AN:

1227090

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

2368

AN XY:

610758

show subpopulations

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

African (AFR)

AF:

0.00203

AC:

AN:

29026

American (AMR)

AF:

0.0145

AC:

508

AN:

35052

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

385

AN:

18606

East Asian (EAS)

AF:

0.0135

AC:

430

AN:

31740

South Asian (SAS)

AF:

0.00449

AC:

344

AN:

76596

European-Finnish (FIN)

AF:

0.00639

AC:

238

AN:

37270

Middle Eastern (MID)

AF:

0.00742

AC:

AN:

3502

European-Non Finnish (NFE)

AF:

0.00249

AC:

2354

AN:

946344

Other (OTH)

AF:

0.00547

AC:

268

AN:

48954

⚠️ 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: 0.358

Heterozygous variant carriers

234

469

703

938

1172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000462

AC:

AN:

51972

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

AN XY:

24642

show subpopulations

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

African (AFR)

AF:

0.000354

AC:

AN:

11310

American (AMR)

AF:

0.000706

AC:

AN:

4252

Ashkenazi Jewish (ASJ)

AF:

0.00175

AC:

AN:

572

East Asian (EAS)

AF:

0.000489

AC:

AN:

2044

South Asian (SAS)

AF:

0.00

AC:

AN:

1254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000540

AC:

AN:

27768

Other (OTH)

AF:

0.00

AC:

AN:

626

⚠️ 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: 0.269

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00948

Hom.:

ExAC

AF:

0.00337

AC:

405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.024

T;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.088

T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.93

PhyloP100

-0.59

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.13

Sift

Benign

0.25

T;.;T

Sift4G

Benign

0.13

T;.;T

Polyphen

0.0050

B;.;.

Vest4

0.16

MVP

0.067

MPC

0.22

ClinPred

0.021

GERP RS

-0.21

Varity_R

0.21

gMVP

0.078

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over