NM_002124.4:c.780G>A

Variant names:

• chr6-32580254-C-T
• rs192487435
• NM_002124.4:c.780G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_002124.4(HLA-DRB1):​c.780G>A​(p.Gln260Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 15)
  • Exomes 𝑓: 0.0000064 (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: -0.160
• Publications: 4 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-32580254-C-T is Benign according to our data. Variant chr6-32580254-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2656457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.16 with no splicing effect.

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.780G>A	p.Gln260Gln	synonymous	Exon 5 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.780G>A	p.Gln260Gln	synonymous	Exon 5 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.858G>A	p.Gln286Gln	synonymous	Exon 5 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859898.1		c.690G>A	p.Gln230Gln	synonymous	Exon 5 of 6	ENSP00000529957.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 106616 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 190876 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000641 AC: 6 AN: 936406 Hom.: 0 Cov.: 15 AF XY: 0.00000626 AC XY: 3 AN XY: 478860

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

African (AFR) AF: 0.00 AC: 0 AN: 24624

American (AMR) AF: 0.00 AC: 0 AN: 31946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18696

East Asian (EAS) AF: 0.00 AC: 0 AN: 26136

South Asian (SAS) AF: 0.00 AC: 0 AN: 68726

European-Finnish (FIN) AF: 0.000109 AC: 5 AN: 45710

Middle Eastern (MID) AF: 0.000260 AC: 1 AN: 3850

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 676332

Other (OTH) AF: 0.00 AC: 0 AN: 40386

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 106722 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 51800

African (AFR) AF: 0.00 AC: 0 AN: 30202

American (AMR) AF: 0.00 AC: 0 AN: 9164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2378

East Asian (EAS) AF: 0.00 AC: 0 AN: 3060

South Asian (SAS) AF: 0.00 AC: 0 AN: 3054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49212

Other (OTH) AF: 0.00 AC: 0 AN: 1400

Alfa AF: 0.0284 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		-0.16
Mutation Taster		=100/0	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: rs192487435; hg19: chr6-32548031; COSMIC: COSV63514500;