dbSNP rs200078051: HLA-DRB1:p.Lys134Asn (chr6-32581807-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002124.4(HLA-DRB1):c.402G>C(p.Lys134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 133,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K134K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000075 ( 0 hom., cov: 23)

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.264

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30807692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4 link	c.402G>C	p.Lys134Asn	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.402G>C	p.Lys134Asn	missense_variant	Exon 3 of 6	6	NM_002124.4	ENSP00000353099.5		P01911

Frequencies

GnomAD3 genomes

AF:

0.00000751

AC:

AN:

133188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000299

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

Cov.:

GnomAD4 genome

AF:

0.00000751

AC:

AN:

133188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64438

show subpopulations

Gnomad4 AFR

AF:

0.0000299

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.81

M_CAP

Benign

0.0039

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.0

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.050

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.046

Polyphen

0.90

Vest4

0.18

MutPred

0.55

Loss of ubiquitination at K134 (P = 0.0224);

MVP

0.30

MPC

1.9

ClinPred

0.98

GERP RS

1.9

Varity_R

0.76

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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