Genetic Variant NM_005514.8:c.206A>G (chr6-31356825-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005514.8(HLA-B):c.206A>G(p.Glu69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,071,252 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0029 ( 22 hom., cov: 0)

Exomes 𝑓: 0.0038 ( 731 hom. )

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.91

Publications

23 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:

ENSG00000271581 (HGNC:):

ENSG00000271581 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033741891).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 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.206A>G	p.Glu69Gly	missense	Exon 2 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.206A>G	p.Glu69Gly	missense	Exon 2 of 8	ENSP00000399168.2	P01889
HLA-B	ENST00000696559.1		c.206A>G	p.Glu69Gly	missense	Exon 5 of 11	ENSP00000512717.1	P01889
HLA-B	ENST00000696560.1		c.206A>G	p.Glu69Gly	missense	Exon 4 of 10	ENSP00000512718.1	P01889

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

109

AN:

37842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000317

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000952

Gnomad OTH

AF:

0.00259

GnomAD2 exomes

AF:

0.00593

AC:

802

AN:

135230

AF XY:

0.00612

show subpopulations

Gnomad AFR exome

AF:

0.000918

Gnomad AMR exome

AF:

0.000840

Gnomad ASJ exome

AF:

0.000311

Gnomad EAS exome

AF:

0.0850

Gnomad FIN exome

AF:

0.00341

Gnomad NFE exome

AF:

0.000623

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00380

AC:

3924

AN:

1033376

Hom.:

731

Cov.:

AF XY:

0.00398

AC XY:

2042

AN XY:

513528

show subpopulations

African (AFR)

AF:

0.00308

AC:

AN:

21764

American (AMR)

AF:

0.00409

AC:

129

AN:

31518

Ashkenazi Jewish (ASJ)

AF:

0.00104

AC:

AN:

20206

East Asian (EAS)

AF:

0.109

AC:

2713

AN:

24890

South Asian (SAS)

AF:

0.00528

AC:

295

AN:

55894

European-Finnish (FIN)

AF:

0.000518

AC:

AN:

34752

Middle Eastern (MID)

AF:

0.00309

AC:

AN:

2910

European-Non Finnish (NFE)

AF:

0.000694

AC:

554

AN:

798804

Other (OTH)

AF:

0.00277

AC:

118

AN:

42638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00290

AC:

110

AN:

37876

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

AN XY:

17462

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

8346

American (AMR)

AF:

0.000315

AC:

AN:

3170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1006

East Asian (EAS)

AF:

0.127

AC:

103

AN:

808

South Asian (SAS)

AF:

0.00206

AC:

AN:

486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000952

AC:

AN:

20998

Other (OTH)

AF:

0.00251

AC:

AN:

398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.583

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00428

AC:

389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.51

CADD

Benign

4.2

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.024

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.0018

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.94

PhyloP100

-4.9

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Benign

0.12

Sift4G

Benign

0.077

Polyphen

0.0

Vest4

0.12

MutPred

0.25

Gain of sheet (P = 0.0477)

MVP

0.055

MPC

0.28

ClinPred

0.019

GERP RS

-6.4

PromoterAI

0.011

Neutral

(source)

Varity_R

0.33

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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