6-32584282-G-T

Position:

• chr6-32584282-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002124.4(HLA-DRB1):​c.197C>A​(p.Ser66Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S66F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.58 (18334 hom., cov: 17)
  • Exomes 𝑓: 0.55 (185262 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.35

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5418816E-5).
• BP6: Variant 6-32584282-G-T is Benign according to our data. Variant chr6-32584282-G-T is described in ClinVar as [Benign]. Clinvar id is 1260112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.197C>A	p.Ser66Tyr	missense_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.197C>A	p.Ser66Tyr	missense_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 65401 AN: 112994 Hom.: 18317 Cov.: 17

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.605

GnomAD3 exomes AF: 0.568 AC: 87771 AN: 154416 Hom.: 29154 AF XY: 0.570 AC XY: 48518 AN XY: 85144

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.672

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.443

Gnomad SAS exome AF: 0.513

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.571

Gnomad OTH exome AF: 0.531

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.553 AC: 630509 AN: 1140416 Hom.: 185262 Cov.: 35 AF XY: 0.555 AC XY: 318346 AN XY: 573406

Gnomad4 AFR exome AF: 0.585

Gnomad4 AMR exome AF: 0.726

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.570

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.579 AC: 65465 AN: 113086 Hom.: 18334 Cov.: 17 AF XY: 0.576 AC XY: 31347 AN XY: 54454

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.603

Alfa AF: 0.449 Hom.: 633

ESP6500AA AF: 0.715 AC: 3132

ESP6500EA AF: 0.685 AC: 5870

ExAC AF: 0.604 AC: 72865

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2019

This variant is associated with the following publications: (PMID: 30084967) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0010
DANN	Benign	0.089
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-4.0
Eigen_PC	Benign	-4.0
FATHMM_MKL	Benign	0.00079	N
LIST_S2	Benign	0.0065	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	3.8	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.16	B
Vest4		0.065
MPC		0.92
ClinPred		0.015	T
GERP RS		-7.0
Varity_R		0.15
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs707957; hg19: chr6-32552059; COSMIC: COSV63511637;