6-32580745-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PVS1_Strong PP3 BP6_Moderate

The NM_002124.4(HLA-DRB1):c.763+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.13732834 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP6: Variant 6-32580745-C-G is Benign according to our data. Variant chr6-32580745-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3024757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.763+1G>C		splice_donor_variant		ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.763+1G>C		splice_donor_variant			NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 322 AN: 140036 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000921

Gnomad AMI AF: 0.00495

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00504

Gnomad EAS AF: 0.00412

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00350

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00107

GnomAD3 exomes AF: 0.0186 AC: 3671 AN: 197302 Hom.: 0 AF XY: 0.0184 AC XY: 1959 AN XY: 106472

Gnomad AFR exome AF: 0.00711

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0169

Gnomad SAS exome AF: 0.00969

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00343 AC: 4444 AN: 1294940 Hom.: 0 Cov.: 56 AF XY: 0.00318 AC XY: 2059 AN XY: 647198

Gnomad4 AFR exome AF: 0.00104

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00143

Gnomad4 EAS exome AF: 0.000455

Gnomad4 SAS exome AF: 0.000431

Gnomad4 FIN exome AF: 0.000292

Gnomad4 NFE exome AF: 0.00417

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00230 AC: 322 AN: 140148 Hom.: 0 Cov.: 27 AF XY: 0.00220 AC XY: 150 AN XY: 68176

Gnomad4 AFR AF: 0.000918

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00504

Gnomad4 EAS AF: 0.00413

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00292

Gnomad4 OTH AF: 0.00106

Alfa AF: 0.0277 Hom.: 0

ExAC AF: 0.101 AC: 12269

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

Feb 01, 2024

HLA-DRB1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	D
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs35121789; hg19: chr6-32548522; COSMIC: COSV63515828;