6-32584282-G-A

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>T(p.Ser66Phe) 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. S66Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.090 (48 hom., cov: 17)
  • Exomes 𝑓: 0.083 (1382 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=0.0015552342).
• BP6: Variant 6-32584282-G-A is Benign according to our data. Variant chr6-32584282-G-A is described in ClinVar as [Benign]. Clinvar id is 1296897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.197C>T	p.Ser66Phe	missense_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.197C>T	p.Ser66Phe	missense_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 10188 AN: 112944 Hom.: 48 Cov.: 17

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0957

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0721

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0795 AC: 12280 AN: 154416 Hom.: 607 AF XY: 0.0826 AC XY: 7035 AN XY: 85144

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.0700

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0734

Gnomad OTH exome AF: 0.0829

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0828 AC: 96890 AN: 1170020 Hom.: 1382 Cov.: 35 AF XY: 0.0843 AC XY: 49505 AN XY: 587120

Gnomad4 AFR exome AF: 0.0921

Gnomad4 AMR exome AF: 0.0564

Gnomad4 ASJ exome AF: 0.0700

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0400

Gnomad4 NFE exome AF: 0.0804

Gnomad4 OTH exome AF: 0.0866

GnomAD4 genome AF: 0.0902 AC: 10198 AN: 113058 Hom.: 48 Cov.: 17 AF XY: 0.0896 AC XY: 4889 AN XY: 54588

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.0721

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.0784

Gnomad4 OTH AF: 0.100

Alfa AF: 0.132 Hom.: 633

ExAC AF: 0.120 AC: 14466

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	0.098
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0010
Dann	Benign	0.20
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-3.9
Eigen_PC	Benign	-3.9
FATHMM_MKL	Benign	0.00069	N
LIST_S2	Benign	0.028	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	2.8	N
REVEL	Benign	0.055
Sift	Benign	0.50	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.78
ClinPred		0.013	T
GERP RS		-7.0
Varity_R		0.21
gMVP		0.23

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: COSV63512983;