dbSNP rs757966595: HLA-DRB1:p.Gly164Arg (chr6-32581719-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_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

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

HLA-DRB1 links:

Genome browser will be placed here

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_002124.4. 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-DRB1	NM_002124.4	MANE Select	c.490G>C	p.Gly164Arg	missense	Exon 3 of 6	NP_002115.2	P01911

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.490G>C	p.Gly164Arg	missense	Exon 3 of 6	ENSP00000353099.5	P01911
HLA-DRB1	ENST00000963203.1		c.568G>C	p.Gly190Arg	missense	Exon 3 of 6	ENSP00000633262.1
HLA-DRB1	ENST00000859900.1		c.490G>C	p.Gly164Arg	missense	Exon 3 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247354

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

26510

American (AMR)

AF:

0.00

AC:

AN:

42622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23918

East Asian (EAS)

AF:

0.00

AC:

AN:

37430

South Asian (SAS)

AF:

0.00

AC:

AN:

80952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5082

European-Non Finnish (NFE)

AF:

0.00000108

AC:

AN:

925192

Other (OTH)

AF:

0.00

AC:

AN:

52478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

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

PhyloP100

1.6

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

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over