Genetic Variant NM_005514.8:c.506G>C (chr6-31356280-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005514.8(HLA-B):c.506G>C(p.Arg169Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,304,094 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 6)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.494

Publications

17 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.506G>C	p.Arg169Pro	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.506G>C	p.Arg169Pro	missense	Exon 3 of 8	ENSP00000399168.2	P01889
HLA-B	ENST00000696559.1		c.506G>C	p.Arg169Pro	missense	Exon 6 of 11	ENSP00000512717.1	P01889
HLA-B	ENST00000696560.1		c.506G>C	p.Arg169Pro	missense	Exon 5 of 10	ENSP00000512718.1	P01889

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

54244

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

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242642

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000660

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000153

AC:

AN:

1304094

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

647998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30326

American (AMR)

AF:

0.00

AC:

AN:

38266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20720

East Asian (EAS)

AF:

0.00

AC:

AN:

33824

South Asian (SAS)

AF:

0.00

AC:

AN:

80322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.00000199

AC:

AN:

1004488

Other (OTH)

AF:

0.00

AC:

AN:

52102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

54244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

25952

African (AFR)

AF:

0.00

AC:

AN:

12024

American (AMR)

AF:

0.00

AC:

AN:

4644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

616

East Asian (EAS)

AF:

0.00

AC:

AN:

2182

South Asian (SAS)

AF:

0.00

AC:

AN:

1450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

28450

Other (OTH)

AF:

0.00

AC:

AN:

626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.018

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.031

M_CAP

Benign

0.0026

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

PhyloP100

-0.49

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.018

Polyphen

0.97

Vest4

0.63

MutPred

0.68

Loss of MoRF binding (P = 0.001)

MVP

0.29

MPC

1.0

ClinPred

0.77

GERP RS

0.27

Varity_R

0.91

gMVP

0.55

Mutation Taster

=100/0

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over