6-32580745-C-T

Variant names:

• chr6-32580745-C-T
• rs35121789
• NM_002124.4:c.763+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002124.4(HLA-DRB1):​c.763+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,551,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: HLA-DRB1 NM_002124.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13857678 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

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.763+1G>A		splice_donor 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.763+1G>A		splice_donor intron	N/A	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.841+1G>A		splice_donor intron	N/A	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.763+1G>A		splice_donor intron	N/A	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.00000700 AC: 1 AN: 142818 Hom.: 0 Cov.: 27

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: 0.0000155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 197302 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 AF: 0.00000497 AC: 7 AN: 1408430 Hom.: 0 Cov.: 56 AF XY: 0.00000570 AC XY: 4 AN XY: 701900

⚠️ 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: 32860

American (AMR) AF: 0.0000232 AC: 1 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 38816

South Asian (SAS) AF: 0.00 AC: 0 AN: 84582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4864

European-Non Finnish (NFE) AF: 0.00000562 AC: 6 AN: 1067776

Other (OTH) AF: 0.00 AC: 0 AN: 58358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000197617), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000700 AC: 1 AN: 142818 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 69356

African (AFR) AF: 0.00 AC: 0 AN: 39392

American (AMR) AF: 0.00 AC: 0 AN: 13758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4756

South Asian (SAS) AF: 0.00 AC: 0 AN: 4474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64382

Other (OTH) AF: 0.00 AC: 0 AN: 1908

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		3.3
GERP RS		4.0
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs35121789; hg19: chr6-32548522;