6-32584351-TCCC-T

Variant names:

• chr6-32584351-TCCC-T
• rs745615811
• NM_002124.4:c.125_127delGGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_002124.4(HLA-DRB1):​c.125_127delGGG​(p.Arg42_Glu43delinsLys) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (0 hom., cov: 11)
  • Exomes 𝑓: 0.0092 (285 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002124.4. Strenght limited to Supporting due to length of the change: 1aa.

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.125_127delGGG	p.Arg42_Glu43delinsLys	disruptive_inframe_deletion	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.125_127delGGG	p.Arg42_Glu43delinsLys	disruptive_inframe_deletion	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.203_205delGGG	p.Arg68_Glu69delinsLys	disruptive_inframe_deletion	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.125_127delGGG	p.Arg42_Glu43delinsLys	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 527 AN: 106882 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.0227

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00638

Gnomad EAS AF: 0.00171

Gnomad SAS AF: 0.00590

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00618

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.0000193 AC: 2 AN: 103648 AF XY: 0.0000174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00921 AC: 6837 AN: 742280 Hom.: 285 AF XY: 0.00975 AC XY: 3745 AN XY: 383954

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00637 AC: 128 AN: 20102

American (AMR) AF: 0.0127 AC: 380 AN: 29878

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 232 AN: 17410

East Asian (EAS) AF: 0.00152 AC: 45 AN: 29676

South Asian (SAS) AF: 0.0149 AC: 955 AN: 63922

European-Finnish (FIN) AF: 0.00550 AC: 221 AN: 40154

Middle Eastern (MID) AF: 0.0502 AC: 199 AN: 3968

European-Non Finnish (NFE) AF: 0.00859 AC: 4309 AN: 501870

Other (OTH) AF: 0.0104 AC: 368 AN: 35300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00491 AC: 525 AN: 106982 Hom.: 0 Cov.: 11 AF XY: 0.00473 AC XY: 245 AN XY: 51812

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00383 AC: 117 AN: 30514

American (AMR) AF: 0.00420 AC: 43 AN: 10246

Ashkenazi Jewish (ASJ) AF: 0.00638 AC: 17 AN: 2664

East Asian (EAS) AF: 0.00171 AC: 6 AN: 3508

South Asian (SAS) AF: 0.00528 AC: 17 AN: 3218

European-Finnish (FIN) AF: 0.00171 AC: 12 AN: 7030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.00616 AC: 293 AN: 47544

Other (OTH) AF: 0.00425 AC: 6 AN: 1412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0486 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple sclerosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=169/31	polymorphism

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

Other links and lift over

dbSNP: rs745615811; hg19: chr6-32552128;