Genetic Variant NM_005514.8:c.419A>G (chr6-31356367-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005514.8(HLA-B):c.419A>G(p.Tyr140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y140S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -8.15

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09888759).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	NM_005514.8	MANE Select	c.419A>G	p.Tyr140Cys	missense	Exon 3 of 8	NP_005505.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.419A>G	p.Tyr140Cys	missense	Exon 3 of 8	ENSP00000399168.2
HLA-B	ENST00000696559.1		c.419A>G	p.Tyr140Cys	missense	Exon 6 of 11	ENSP00000512717.1
HLA-B	ENST00000696560.1		c.419A>G	p.Tyr140Cys	missense	Exon 5 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

37068

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

913476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

458326

African (AFR)

AF:

0.00

AC:

AN:

20412

American (AMR)

AF:

0.00

AC:

AN:

28814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12778

East Asian (EAS)

AF:

0.00

AC:

AN:

27260

South Asian (SAS)

AF:

0.00

AC:

AN:

60362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2344

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

695800

Other (OTH)

AF:

0.00

AC:

AN:

36234

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

37068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

17522

African (AFR)

AF:

0.00

AC:

AN:

8412

American (AMR)

AF:

0.00

AC:

AN:

3114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

374

East Asian (EAS)

AF:

0.00

AC:

AN:

1330

South Asian (SAS)

AF:

0.00

AC:

AN:

750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

19908

Other (OTH)

AF:

0.00

AC:

AN:

380

Alfa

AF:

0.00

Hom.:

295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.16

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.041

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.039

M_CAP

Benign

0.0012

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.76

PhyloP100

-8.1

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.24

Sift

Benign

0.050

Sift4G

Benign

0.10

Polyphen

0.93

Vest4

0.35

MutPred

0.12

Loss of phosphorylation at Y140 (P = 0.0534)

MVP

0.030

MPC

0.81

ClinPred

0.35

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over