6-31356423-G-C

Position:

chr6-31356423-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_005514.8(HLA-B):c.363C>G(p.Ser121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict 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. S121N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.35 ( 4536 hom., cov: 3)

Exomes 𝑓: 0.43 ( 113105 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.84

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=2.1657443E-6).

BP6

Variant 6-31356423-G-C is Benign according to our data. Variant chr6-31356423-G-C is described in ClinVar as [Benign]. Clinvar id is 3059612.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-B	NM_005514.8 linkuse as main transcript	c.363C>G	p.Ser121Arg	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.363C>G	p.Ser121Arg	missense_variant	3/8		NM_005514.8	ENSP00000399168	P1

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

11578

AN:

33360

Hom.:

4534

Cov.:

show subpopulations

Gnomad AFR

AF:

0.370

Gnomad AMI

AF:

0.473

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.265

Gnomad EAS

AF:

0.774

Gnomad SAS

AF:

0.317

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.710

AC:

125997

AN:

177552

Hom.:

51124

AF XY:

0.710

AC XY:

68480

AN XY:

96486

show subpopulations

Gnomad AFR exome

AF:

0.712

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.823

Gnomad EAS exome

AF:

0.903

Gnomad SAS exome

AF:

0.784

Gnomad FIN exome

AF:

0.642

Gnomad NFE exome

AF:

0.647

Gnomad OTH exome

AF:

0.725

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.428

AC:

299975

AN:

701228

Hom.:

113105

Cov.:

AF XY:

0.441

AC XY:

154750

AN XY:

350816

show subpopulations

Gnomad4 AFR exome

AF:

0.563

Gnomad4 AMR exome

AF:

0.537

Gnomad4 ASJ exome

AF:

0.668

Gnomad4 EAS exome

AF:

0.743

Gnomad4 SAS exome

AF:

0.727

Gnomad4 FIN exome

AF:

0.389

Gnomad4 NFE exome

AF:

0.378

Gnomad4 OTH exome

AF:

0.448

GnomAD4 genome

AF:

0.347

AC:

11584

AN:

33368

Hom.:

4536

Cov.:

AF XY:

0.344

AC XY:

5343

AN XY:

15510

show subpopulations

Gnomad4 AFR

AF:

0.370

Gnomad4 AMR

AF:

0.249

Gnomad4 ASJ

AF:

0.265

Gnomad4 EAS

AF:

0.775

Gnomad4 SAS

AF:

0.320

Gnomad4 FIN

AF:

0.327

Gnomad4 NFE

AF:

0.324

Gnomad4 OTH

AF:

0.358

Alfa

AF:

0.584

Hom.:

3333

ESP6500AA

AF:

0.600

AC:

2178

ESP6500EA

AF:

0.596

AC:

4707

ExAC

AF:

0.643

AC:

71782

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

0.18

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.1

DANN

Benign

0.51

DEOGEN2

Benign

0.016

T;.;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.0043

T;T;T

MetaRNN

Benign

0.0000022

T;T;T

MetaSVM

Benign

-0.89

MutationTaster

Benign

1.0

PROVEAN

Benign

1.1

N;.;N

REVEL

Benign

0.24

Sift

Benign

1.0

T;.;T

Sift4G

Benign

0.70

T;.;T

Polyphen

0.071

B;.;.

Vest4

0.062

MutPred

0.083

Gain of phosphorylation at T118 (P = 0.1034);Gain of phosphorylation at T118 (P = 0.1034);.;

MPC

0.27

ClinPred

0.0014

GERP RS

-2.7

Varity_R

0.17

gMVP

0.21

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

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