dbSNP rs1131204: HLA-B:p.Ala93Pro (chr6-31356754-C-G) – 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.277G>C(p.Ala93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 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. A93T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 5)

Exomes 𝑓: 0.0050 ( 19 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027052164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.277G>C	p.Ala93Pro	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>C	p.Ala93Pro	missense_variant	Exon 2 of 8	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

43104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000557

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00272

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000457

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00271

AC:

529

AN:

195270

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0424

Gnomad FIN exome

AF:

0.0000597

Gnomad NFE exome

AF:

0.0000232

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00498

AC:

4804

AN:

965400

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

2427

AN XY:

479476

show subpopulations

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

African (AFR)

AF:

0.00508

AC:

AN:

18298

American (AMR)

AF:

0.00418

AC:

129

AN:

30828

Ashkenazi Jewish (ASJ)

AF:

0.00193

AC:

AN:

18622

East Asian (EAS)

AF:

0.0198

AC:

436

AN:

21998

South Asian (SAS)

AF:

0.00741

AC:

394

AN:

53138

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

31558

Middle Eastern (MID)

AF:

0.00264

AC:

AN:

2656

European-Non Finnish (NFE)

AF:

0.00470

AC:

3519

AN:

748974

Other (OTH)

AF:

0.00376

AC:

148

AN:

39328

⚠️ 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: 0.286

Heterozygous variant carriers

472

943

1415

1886

2358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.000232

AC:

AN:

43156

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

20360

show subpopulations

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

African (AFR)

AF:

0.000555

AC:

AN:

10802

American (AMR)

AF:

0.00

AC:

AN:

3782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1344

East Asian (EAS)

AF:

0.00274

AC:

AN:

1096

South Asian (SAS)

AF:

0.00

AC:

AN:

674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000457

AC:

AN:

21896

Other (OTH)

AF:

0.00

AC:

AN:

486

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000100393), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

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:

0.000437

Hom.:

3628

ExAC

AF:

0.00215

AC:

255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.047

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.037

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-3.3

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;.;D

Sift4G

Benign

0.064

T;.;T

Polyphen

0.60

P;.;.

Vest4

0.27

MVP

0.040

MPC

0.70

ClinPred

0.16

GERP RS

-2.7

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.49

gMVP

0.31

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