dbSNP rs12697943: HLA-B:p.Arg169Leu (chr6-31356280-C-A) – 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.506G>T(p.Arg169Leu) 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. 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.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 6)

Exomes 𝑓: 0.0043 ( 18 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.494

Publications

17 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=0.009438276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.506G>T	p.Arg169Leu	missense_variant	Exon 3 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.506G>T	p.Arg169Leu	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

AN:

54056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000583

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000862

Gnomad ASJ

AF:

0.00487

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.00347

Gnomad FIN

AF:

0.000512

Gnomad MID

AF:

0.0114

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00161

GnomAD2 exomes

AF:

0.0174

AC:

4232

AN:

242642

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.00627

Gnomad AMR exome

AF:

0.00782

Gnomad ASJ exome

AF:

0.0241

Gnomad EAS exome

AF:

0.0567

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00427

AC:

5536

AN:

1297578

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

2953

AN XY:

644546

show subpopulations

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

African (AFR)

AF:

0.00192

AC:

AN:

30266

American (AMR)

AF:

0.00297

AC:

113

AN:

38080

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

247

AN:

20548

East Asian (EAS)

AF:

0.0165

AC:

550

AN:

33282

South Asian (SAS)

AF:

0.0105

AC:

836

AN:

79502

European-Finnish (FIN)

AF:

0.00796

AC:

316

AN:

39714

Middle Eastern (MID)

AF:

0.00748

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00311

AC:

3114

AN:

1000376

Other (OTH)

AF:

0.00525

AC:

272

AN:

51800

⚠️ 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: 0.399

Heterozygous variant carriers

214

428

641

855

1069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00172

AC:

AN:

54068

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

AN XY:

25902

show subpopulations

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

African (AFR)

AF:

0.000581

AC:

AN:

12040

American (AMR)

AF:

0.000860

AC:

AN:

4652

Ashkenazi Jewish (ASJ)

AF:

0.00487

AC:

AN:

616

East Asian (EAS)

AF:

0.00889

AC:

AN:

2138

South Asian (SAS)

AF:

0.00351

AC:

AN:

1424

European-Finnish (FIN)

AF:

0.000512

AC:

AN:

3906

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00176

AC:

AN:

28340

Other (OTH)

AF:

0.00314

AC:

AN:

636

⚠️ 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: 0.338

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:

0.00981

Hom.:

ExAC

AF:

0.0190

AC:

2291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.016

T;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.037

T;T;T

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.49

PROVEAN

Pathogenic

-5.5

D;.;D

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.020

D;.;D

Polyphen

0.0070

B;.;.

Vest4

0.12

MPC

0.93

ClinPred

0.079

GERP RS

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.72

gMVP

0.24

Mutation Taster

=100/0

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

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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