Genetic Variant HLA-DRB5:p.Asp66His (chr6-32522079-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002125.4(HLA-DRB5):c.196G>C(p.Asp66His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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. D66N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 13)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.46

Publications

25 publications found

Variant links:

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

HLA-DRB5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057871282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4 link	c.196G>C	p.Asp66His	missense_variant	Exon 2 of 6	ENST00000374975.4	NP_002116.2	Q30154A0A2Z4LKS3
HLA-DRB5	XM_011514562.3 link	c.196G>C	p.Asp66His	missense_variant	Exon 2 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4 link	c.196G>C	p.Asp66His	missense_variant	Exon 2 of 6	6	NM_002125.4	ENSP00000364114.3		Q30154
HLA-DRB5	ENST00000714490.1 link	c.196G>C	p.Asp66His	missense_variant	Exon 2 of 6			ENSP00000519744.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

94930

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:

1251064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

625924

African (AFR)

AF:

0.00

AC:

AN:

26842

American (AMR)

AF:

0.00

AC:

AN:

41980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22922

East Asian (EAS)

AF:

0.00

AC:

AN:

35982

South Asian (SAS)

AF:

0.00

AC:

AN:

74998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4928

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

943440

Other (OTH)

AF:

0.00

AC:

AN:

52022

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

94930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

45222

African (AFR)

AF:

0.00

AC:

AN:

22714

American (AMR)

AF:

0.00

AC:

AN:

8676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2124

East Asian (EAS)

AF:

0.00

AC:

AN:

3180

South Asian (SAS)

AF:

0.00

AC:

AN:

2544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

158

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47464

Other (OTH)

AF:

0.00

AC:

AN:

1170

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0010

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.0071

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.10

M_CAP

Benign

0.0018

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.76

PhyloP100

-4.5

PrimateAI

Benign

0.29

PROVEAN

Benign

2.1

REVEL

Benign

0.13

Sift

Benign

0.17

Sift4G

Benign

0.12

Polyphen

0.59

Vest4

0.13

MutPred

0.10

Gain of sheet (P = 0.0827);

MVP

0.055

MPC

0.018

ClinPred

0.83

GERP RS

-9.6

Varity_R

0.29

gMVP

0.33

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over