Genetic Variant HLA-DRB1:p.Gln260His (chr6-32580254-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002124.4(HLA-DRB1):c.780G>T(p.Gln260His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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. Q260P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 15)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.160

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11606884).

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.780G>T	p.Gln260His	missense	Exon 5 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.780G>T	p.Gln260His	missense	Exon 5 of 6	ENSP00000353099.5	P01911
HLA-DRB1	ENST00000963203.1		c.858G>T	p.Gln286His	missense	Exon 5 of 6	ENSP00000633262.1
HLA-DRB1	ENST00000859898.1		c.690G>T	p.Gln230His	missense	Exon 5 of 6	ENSP00000529957.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

936446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

478880

African (AFR)

AF:

0.00

AC:

AN:

24622

American (AMR)

AF:

0.00

AC:

AN:

31954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18698

East Asian (EAS)

AF:

0.00

AC:

AN:

26136

South Asian (SAS)

AF:

0.00

AC:

AN:

68730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3850

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

676342

Other (OTH)

AF:

0.00

AC:

AN:

40388

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0059

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.60

M_CAP

Benign

0.0036

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

PhyloP100

-0.16

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.051

Sift4G

Uncertain

0.025

Polyphen

0.0

Vest4

0.31

MutPred

0.24

Gain of glycosylation at S257 (P = 0.0718)

MVP

0.36

MPC

0.69

ClinPred

0.19

GERP RS

2.1

Varity_R

0.073

gMVP

0.20

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over