NM_005514.8:c.363C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. S121S) has been classified as Uncertain significance.

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

Publications

28 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:

ENSG00000298426 (HGNC:):

ENSG00000298426 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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.363C>G	p.Ser121Arg	missense	Exon 3 of 8	NP_005505.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.363C>G	p.Ser121Arg	missense	Exon 3 of 8	ENSP00000399168.2	P01889
HLA-B	ENST00000696559.1		c.363C>G	p.Ser121Arg	missense	Exon 6 of 11	ENSP00000512717.1	P01889
HLA-B	ENST00000696560.1		c.363C>G	p.Ser121Arg	missense	Exon 5 of 10	ENSP00000512718.1	P01889

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

GnomAD2 exomes

AF:

0.710

AC:

125997

AN:

177552

AF XY:

0.710

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 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

African (AFR)

AF:

0.563

AC:

8569

AN:

15218

American (AMR)

AF:

0.537

AC:

11326

AN:

21074

Ashkenazi Jewish (ASJ)

AF:

0.668

AC:

5652

AN:

8466

East Asian (EAS)

AF:

0.743

AC:

16023

AN:

21562

South Asian (SAS)

AF:

0.727

AC:

32750

AN:

45024

European-Finnish (FIN)

AF:

0.389

AC:

8385

AN:

21546

Middle Eastern (MID)

AF:

0.645

AC:

914

AN:

1416

European-Non Finnish (NFE)

AF:

0.378

AC:

204039

AN:

539408

Other (OTH)

AF:

0.448

AC:

12317

AN:

27514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

3231

6463

9694

12926

16157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4732

9464

14196

18928

23660

<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:

0.347

AC:

11584

AN:

33368

Hom.:

4536

Cov.:

AF XY:

0.344

AC XY:

5343

AN XY:

15510

show subpopulations

African (AFR)

AF:

0.370

AC:

2939

AN:

7952

American (AMR)

AF:

0.249

AC:

615

AN:

2468

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

AN:

260

East Asian (EAS)

AF:

0.775

AC:

978

AN:

1262

South Asian (SAS)

AF:

0.320

AC:

139

AN:

434

European-Finnish (FIN)

AF:

0.327

AC:

793

AN:

2426

Middle Eastern (MID)

AF:

0.583

AC:

AN:

European-Non Finnish (NFE)

AF:

0.324

AC:

5845

AN:

18054

Other (OTH)

AF:

0.358

AC:

121

AN:

338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.584

Hom.:

3333

ESP6500AA

AF:

0.600

AC:

2178

ESP6500EA

AF:

0.596

AC:

4707

ExAC

AF:

0.643

AC:

71782

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

HLA-B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.1

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.016

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.0043

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-0.89

PhyloP100

-1.8

PROVEAN

Benign

1.1

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

0.70

Polyphen

0.071

Vest4

0.062

MutPred

0.083

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over