chr6-31356367-T-G

Position:

chr6-31356367-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005514.8(HLA-B):c.419A>C(p.Tyr140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y140D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 82 hom., cov: 3)

Exomes 𝑓: 0.16 ( 16503 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -8.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008836359).

BP6

Variant 6-31356367-T-G is Benign according to our data. Variant chr6-31356367-T-G is described in ClinVar as [Benign]. Clinvar id is 3060941.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0192 (690/35974) while in subpopulation AMR AF= 0.0525 (160/3046). AF 95% confidence interval is 0.0459. There are 82 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 3. This position pass quality control queck.

BS2

High AC in GnomAd4 at 690 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-B	NM_005514.8 linkuse as main transcript	c.419A>C	p.Tyr140Ser	missense_variant	3/8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7 linkuse as main transcript	c.419A>C	p.Tyr140Ser	missense_variant	3/8		NM_005514.8	ENSP00000399168	P1

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

685

AN:

35964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.0149

Gnomad AMR

AF:

0.0501

Gnomad ASJ

AF:

0.0160

Gnomad EAS

AF:

0.0521

Gnomad SAS

AF:

0.0123

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.0247

GnomAD3 exomes

AF:

0.215

AC:

40300

AN:

187878

Hom.:

3187

AF XY:

0.212

AC XY:

21755

AN XY:

102434

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.323

Gnomad SAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.213

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.160

AC:

136244

AN:

850840

Hom.:

16503

Cov.:

AF XY:

0.160

AC XY:

68396

AN XY:

427478

show subpopulations

Gnomad4 AFR exome

AF:

0.279

Gnomad4 AMR exome

AF:

0.161

Gnomad4 ASJ exome

AF:

0.202

Gnomad4 EAS exome

AF:

0.104

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.0758

Gnomad4 NFE exome

AF:

0.159

Gnomad4 OTH exome

AF:

0.157

GnomAD4 genome

AF:

0.0192

AC:

690

AN:

35974

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

340

AN XY:

17018

show subpopulations

Gnomad4 AFR

AF:

0.0238

Gnomad4 AMR

AF:

0.0525

Gnomad4 ASJ

AF:

0.0160

Gnomad4 EAS

AF:

0.0508

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.0141

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.149

Hom.:

295

ESP6500AA

AF:

0.250

AC:

1047

ESP6500EA

AF:

0.185

AC:

1548

ExAC

AF:

0.184

AC:

21829

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HLA-B-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.0050

DANN

Benign

0.30

DEOGEN2

Benign

0.017

T;.;T

Eigen

Benign

-3.2

Eigen_PC

Benign

-3.3

FATHMM_MKL

Benign

0.0075

LIST_S2

Benign

0.0056

T;T;T

MetaRNN

Benign

0.0088

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-2.8

D;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.49

T;.;T

Sift4G

Benign

0.36

T;.;T

Polyphen

0.0

B;.;.

Vest4

0.053

MPC

0.36

ClinPred

0.018

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over