dbSNP rs757966595: HLA-DRB1:p.Gly164Arg (chr6-32581719-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002124.4(HLA-DRB1):c.490G>C(p.Gly164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 in 1,245,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G164S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 17)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), 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. It is encoded by 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. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

HLA-DRB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4 link	c.490G>C	p.Gly164Arg	missense_variant	Exon 3 of 6	ENST00000360004.6	NP_002115.2	P01911D7RIH8A0A224MM52X5DNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6 link	c.490G>C	p.Gly164Arg	missense_variant	Exon 3 of 6	6	NM_002124.4	ENSP00000353099.5		P01911

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247354

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.03e-7

AC:

AN:

1245856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

627686

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

0.15

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0090

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.81

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.30

MutPred

0.60

Gain of solvent accessibility (P = 0.1319);

MVP

0.69

MPC

1.7

ClinPred

0.99

GERP RS

3.9

Varity_R

0.86

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over