6-32584143-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_002124.4(HLA-DRB1):c.336C>T(p.Tyr112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,017,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (0 hom., cov: 3)
  • Exomes 𝑓: 0.00076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.132

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-32584143-G-A is Benign according to our data. Variant chr6-32584143-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.336C>T	p.Tyr112=	synonymous_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.336C>T	p.Tyr112=	synonymous_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 277 AN: 56304 Hom.: 0 Cov.: 3 FAILED QC

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.0140

Gnomad AMR AF: 0.00769

Gnomad ASJ AF: 0.00947

Gnomad EAS AF: 0.00698

Gnomad SAS AF: 0.00758

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.00499

Gnomad OTH AF: 0.00420

GnomAD4 exome AF: 0.000764 AC: 777 AN: 1017536 Hom.: 0 Cov.: 32 AF XY: 0.000812 AC XY: 414 AN XY: 509784

Gnomad4 AFR exome AF: 0.000679

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00162

Gnomad4 EAS exome AF: 0.00182

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.000585

Gnomad4 NFE exome AF: 0.000574

Gnomad4 OTH exome AF: 0.000952

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00492 AC: 277 AN: 56342 Hom.: 0 Cov.: 3 AF XY: 0.00475 AC XY: 129 AN XY: 27162

Gnomad4 AFR AF: 0.00345

Gnomad4 AMR AF: 0.00769

Gnomad4 ASJ AF: 0.00947

Gnomad4 EAS AF: 0.00703

Gnomad4 SAS AF: 0.00759

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00499

Gnomad4 OTH AF: 0.00409

Alfa AF: 0.219 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

HLA-DRB1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	11
Dann	Benign	0.40

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: rs45542832; hg19: chr6-32551920; COSMIC: COSV63511227;