Genetic Variant HLA-B:p.Glu187Ala (chr6-31356226-T-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.560A>C(p.Glu187Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.083 ( 162 hom., cov: 4)

Exomes 𝑓: 0.33 ( 34938 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -8.96

Publications

34 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=0.0055871606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.560A>C	p.Glu187Ala	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.560A>C	p.Glu187Ala	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.0833

AC:

2800

AN:

33632

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0724

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.0616

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.0323

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.0781

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.347

AC:

58992

AN:

170240

AF XY:

0.354

show subpopulations

Gnomad AFR exome

AF:

0.322

Gnomad AMR exome

AF:

0.339

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.305

Gnomad NFE exome

AF:

0.360

Gnomad OTH exome

AF:

0.361

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.333

AC:

293181

AN:

880754

Hom.:

34938

Cov.:

AF XY:

0.338

AC XY:

150111

AN XY:

443574

show subpopulations

African (AFR)

AF:

0.304

AC:

6660

AN:

21942

American (AMR)

AF:

0.318

AC:

9289

AN:

29176

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

7333

AN:

15366

East Asian (EAS)

AF:

0.217

AC:

5556

AN:

25630

South Asian (SAS)

AF:

0.418

AC:

27046

AN:

64656

European-Finnish (FIN)

AF:

0.204

AC:

5946

AN:

29124

Middle Eastern (MID)

AF:

0.433

AC:

1205

AN:

2782

European-Non Finnish (NFE)

AF:

0.333

AC:

218086

AN:

655688

Other (OTH)

AF:

0.331

AC:

12060

AN:

36390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

5396

10791

16187

21582

26978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7758

15516

23274

31032

38790

<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:

0.0832

AC:

2799

AN:

33636

Hom.:

162

Cov.:

AF XY:

0.0773

AC XY:

1223

AN XY:

15816

show subpopulations

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

African (AFR)

AF:

0.104

AC:

705

AN:

6798

American (AMR)

AF:

0.0722

AC:

201

AN:

2784

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

AN:

356

East Asian (EAS)

AF:

0.0621

AC:

AN:

1402

South Asian (SAS)

AF:

0.187

AC:

152

AN:

814

European-Finnish (FIN)

AF:

0.0323

AC:

AN:

2538

Middle Eastern (MID)

AF:

0.172

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0781

AC:

1435

AN:

18368

Other (OTH)

AF:

0.124

AC:

AN:

386

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.304

Hom.:

515

ExAC

AF:

0.312

AC:

37388

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.033

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.030

T;.;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.0027

T;T;T

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-0.92

PhyloP100

-9.0

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.22

Sift

Benign

0.10

T;.;T

Sift4G

Benign

0.52

T;.;T

Polyphen

0.0080

B;.;.

Vest4

0.034

MPC

0.25

ClinPred

0.020

GERP RS

-6.4

Varity_R

0.53

gMVP

0.28

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

Computational scores

Splicing

Publications

Other links and lift over