6-32581763-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002124.4(HLA-DRB1):c.446G>A(p.Ser149Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,160,604 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (0 hom., cov: 23)
  • Exomes 𝑓: 0.16 (79 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 6-32581763-C-T is Benign according to our data. Variant chr6-32581763-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3060198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.446G>A	p.Ser149Asn	missense_variant	3/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.446G>A	p.Ser149Asn	missense_variant	3/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 22612 AN: 122866 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.155 AC: 161026 AN: 1037648 Hom.: 79 Cov.: 42 AF XY: 0.151 AC XY: 78686 AN XY: 519762

Gnomad4 AFR exome AF: 0.0720

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.252

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.184 AC: 22624 AN: 122956 Hom.: 0 Cov.: 23 AF XY: 0.184 AC XY: 11004 AN XY: 59686

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.186

Alfa AF: 0.197 Hom.: 7

ExAC AF: 0.188 AC: 22820

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-DRB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.058
Dann	Benign	0.32
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.033	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.020
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.68
ClinPred		0.0020	T
GERP RS		0.026
Varity_R		0.13
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1059351; hg19: chr6-32549540; COSMIC: COSV63511185;