dbSNP rs17839985: HLA-B:p.Asp153Asp (chr6-31356327-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_005514.8(HLA-B):c.459C>T(p.Asp153Asp) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 5)

Exomes 𝑓: 0.047 ( 1382 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.256

Publications

7 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP7

Synonymous conserved (PhyloP=-0.256 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.459C>T	p.Asp153Asp	synonymous_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.459C>T	p.Asp153Asp	synonymous_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

153

AN:

46054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.00360

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.000784

Gnomad FIN

AF:

0.00411

Gnomad MID

AF:

0.0167

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00205

GnomAD2 exomes

AF:

0.165

AC:

33081

AN:

200694

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.143

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.270

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0469

AC:

51932

AN:

1107442

Hom.:

1382

Cov.:

AF XY:

0.0478

AC XY:

26415

AN XY:

552328

show subpopulations

African (AFR)

AF:

0.0965

AC:

2264

AN:

23466

American (AMR)

AF:

0.0777

AC:

2411

AN:

31046

Ashkenazi Jewish (ASJ)

AF:

0.0948

AC:

1630

AN:

17200

East Asian (EAS)

AF:

0.0245

AC:

713

AN:

29080

South Asian (SAS)

AF:

0.0631

AC:

4415

AN:

70006

European-Finnish (FIN)

AF:

0.0380

AC:

1281

AN:

33676

Middle Eastern (MID)

AF:

0.0655

AC:

219

AN:

3342

European-Non Finnish (NFE)

AF:

0.0432

AC:

36986

AN:

855370

Other (OTH)

AF:

0.0455

AC:

2013

AN:

44256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

1677

3355

5032

6710

8387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1650

3300

4950

6600

8250

<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:

0.00334

AC:

154

AN:

46064

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

AN XY:

21886

show subpopulations

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

African (AFR)

AF:

0.00440

AC:

AN:

10228

American (AMR)

AF:

0.00653

AC:

AN:

3826

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

556

East Asian (EAS)

AF:

0.00385

AC:

AN:

1820

South Asian (SAS)

AF:

0.000790

AC:

AN:

1266

European-Finnish (FIN)

AF:

0.00411

AC:

AN:

3160

Middle Eastern (MID)

AF:

0.0179

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00241

AC:

AN:

24468

Other (OTH)

AF:

0.00200

AC:

AN:

500

⚠️ 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: 0.290

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:

0.102

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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