6-32581719-C-T

Position:

• chr6-32581719-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002124.4(HLA-DRB1):​c.490G>A​(p.Gly164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.55

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008397281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.490G>A	p.Gly164Ser	missense_variant	3/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.490G>A	p.Gly164Ser	missense_variant	3/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1022 AN: 116792 Hom.: 0 Cov.: 17 FAILED QC

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00485

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00726

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00410

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00287 AC: 709 AN: 247354 Hom.: 0 AF XY: 0.00274 AC XY: 368 AN XY: 134114

Gnomad AFR exome AF: 0.00813

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00634

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00182 AC: 2239 AN: 1228874 Hom.: 0 Cov.: 33 AF XY: 0.00176 AC XY: 1090 AN XY: 619346

Gnomad4 AFR exome AF: 0.00339

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000866

Gnomad4 FIN exome AF: 0.000350

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00876 AC: 1024 AN: 116886 Hom.: 0 Cov.: 17 AF XY: 0.00877 AC XY: 498 AN XY: 56772

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00726

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00134

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00748

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00616 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.17
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.035	D
Polyphen		0.11	B
Vest4		0.28
MVP		0.29
MPC		1.4
ClinPred		0.081	T
GERP RS		3.9
Varity_R		0.56
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs757966595; hg19: chr6-32549496;