NM_002124.4:c.652+3G>T

Variant names:

• chr6-32581554-C-A
• rs34309628
• NM_002124.4:c.652+3G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_002124.4(HLA-DRB1):​c.652+3G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (1283 hom., cov: 10)
  • Exomes 𝑓: 0.14 (4117 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 splice_region, intron
• Scores: Splicing: ADA: 0.9631
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.828
• Publications: 11 publications found

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]

HLA-DRB1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.652+3G>T		splice_region intron	N/A	NP_002115.2	P01911

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.652+3G>T		splice_region intron	N/A	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.730+3G>T		splice_region intron	N/A	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.652+3G>T		splice_region intron	N/A	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 14468 AN: 73862 Hom.: 1283 Cov.: 10

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.208

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.139 AC: 24996 AN: 179480 AF XY: 0.137

Gnomad AFR exome AF: 0.0727

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.151

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.144 AC: 132636 AN: 922738 Hom.: 4117 Cov.: 17 AF XY: 0.148 AC XY: 69105 AN XY: 466442

African (AFR) AF: 0.0879 AC: 2124 AN: 24156

American (AMR) AF: 0.290 AC: 9747 AN: 33638

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 4426 AN: 17626

East Asian (EAS) AF: 0.283 AC: 8008 AN: 28288

South Asian (SAS) AF: 0.155 AC: 9649 AN: 62078

European-Finnish (FIN) AF: 0.220 AC: 8186 AN: 37248

Middle Eastern (MID) AF: 0.193 AC: 743 AN: 3842

European-Non Finnish (NFE) AF: 0.123 AC: 83353 AN: 676364

Other (OTH) AF: 0.162 AC: 6400 AN: 39498

GnomAD4 genome AF: 0.196 AC: 14490 AN: 73934 Hom.: 1283 Cov.: 10 AF XY: 0.191 AC XY: 6790 AN XY: 35526

African (AFR) AF: 0.108 AC: 2216 AN: 20572

American (AMR) AF: 0.246 AC: 1484 AN: 6038

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 460 AN: 1606

East Asian (EAS) AF: 0.243 AC: 626 AN: 2578

South Asian (SAS) AF: 0.167 AC: 375 AN: 2248

European-Finnish (FIN) AF: 0.190 AC: 815 AN: 4300

Middle Eastern (MID) AF: 0.210 AC: 26 AN: 124

European-Non Finnish (NFE) AF: 0.232 AC: 8141 AN: 35138

Other (OTH) AF: 0.212 AC: 187 AN: 884

Alfa AF: 0.119 Hom.: 64

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.9
DANN	Benign	0.58
PhyloP100		0.83
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.58		Position offset: 3

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

Other links and lift over

dbSNP: rs34309628; hg19: chr6-32549331; COSMIC: COSV63516870;