6-32584361-G-GTA

Variant names:

• chr6-32584361-G-GTA
• rs749085224
• NM_002124.4:c.117_118insTA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_002124.4(HLA-DRB1):​c.117_118insTA​(p.Pro40TyrfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.33 (1764 hom., cov: 0)
  • Exomes 𝑓: 0.24 (24327 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.35
• Publications: 3 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 -9 ACMG points.

• BP6: Variant 6-32584361-G-GTA is Benign according to our data. Variant chr6-32584361-G-GTA is described in ClinVar as Likely_benign. ClinVar VariationId is 3059842.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 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.117_118insTA	p.Pro40TyrfsTer41	frameshift	Exon 2 of 6	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.117_118insTA	p.Pro40TyrfsTer41	frameshift	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.195_196insTA	p.Pro66TyrfsTer41	frameshift	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.117_118insTA	p.Pro40TyrfsTer41	frameshift	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 23349 AN: 71482 Hom.: 1763 Cov.: 0

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.351

GnomAD2 exomes AF: 0.212 AC: 13681 AN: 64458 AF XY: 0.219

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.0883

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.264

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.235 AC: 159552 AN: 678578 Hom.: 24327 Cov.: 11 AF XY: 0.243 AC XY: 85596 AN XY: 351856

African (AFR) AF: 0.356 AC: 6390 AN: 17962

American (AMR) AF: 0.439 AC: 12370 AN: 28200

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 6237 AN: 16264

East Asian (EAS) AF: 0.333 AC: 8701 AN: 26148

South Asian (SAS) AF: 0.276 AC: 16379 AN: 59364

European-Finnish (FIN) AF: 0.334 AC: 11919 AN: 35720

Middle Eastern (MID) AF: 0.337 AC: 1239 AN: 3678

European-Non Finnish (NFE) AF: 0.192 AC: 87906 AN: 458640

Other (OTH) AF: 0.258 AC: 8411 AN: 32602

GnomAD4 genome AF: 0.327 AC: 23381 AN: 71564 Hom.: 1764 Cov.: 0 AF XY: 0.327 AC XY: 11277 AN XY: 34520

African (AFR) AF: 0.382 AC: 7993 AN: 20900

American (AMR) AF: 0.371 AC: 2375 AN: 6402

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 665 AN: 1866

East Asian (EAS) AF: 0.323 AC: 738 AN: 2286

South Asian (SAS) AF: 0.244 AC: 489 AN: 2008

European-Finnish (FIN) AF: 0.308 AC: 1435 AN: 4662

Middle Eastern (MID) AF: 0.416 AC: 69 AN: 166

European-Non Finnish (NFE) AF: 0.288 AC: 9215 AN: 31968

Other (OTH) AF: 0.349 AC: 314 AN: 900

Alfa AF: 0.398 Hom.: 45

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HLA-DRB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=192/8	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs749085224; hg19: chr6-32552138;