6-32580745-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PVS1_Strong BP6_Moderate

The NM_002124.4(HLA-DRB1):​c.763+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 2 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.
• BP6: Variant 6-32580745-C-G is Benign according to our data. Variant chr6-32580745-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3024757.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 322 AN: 140036 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000921

Gnomad AMI AF: 0.00495

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00504

Gnomad EAS AF: 0.00412

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00350

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00107

GnomAD2 exomes AF: 0.0186 AC: 3671 AN: 197302 AF XY: 0.0184

Gnomad AFR exome AF: 0.00711

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0169

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00343 AC: 4444 AN: 1294940 Hom.: 0 Cov.: 56 AF XY: 0.00318 AC XY: 2059 AN XY: 647198

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

African (AFR) AF: 0.00104 AC: 33 AN: 31730

American (AMR) AF: 0.00253 AC: 98 AN: 38698

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 34 AN: 23850

East Asian (EAS) AF: 0.000455 AC: 17 AN: 37356

South Asian (SAS) AF: 0.000431 AC: 35 AN: 81184

European-Finnish (FIN) AF: 0.000292 AC: 15 AN: 51418

Middle Eastern (MID) AF: 0.000851 AC: 4 AN: 4700

European-Non Finnish (NFE) AF: 0.00417 AC: 4049 AN: 971328

Other (OTH) AF: 0.00291 AC: 159 AN: 54676

⚠️ 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: AS_VQSR AF: 0.00230 AC: 322 AN: 140148 Hom.: 0 Cov.: 27 AF XY: 0.00220 AC XY: 150 AN XY: 68176

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

African (AFR) AF: 0.000918 AC: 36 AN: 39196

American (AMR) AF: 0.00341 AC: 46 AN: 13484

Ashkenazi Jewish (ASJ) AF: 0.00504 AC: 16 AN: 3174

East Asian (EAS) AF: 0.00413 AC: 19 AN: 4600

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4424

European-Finnish (FIN) AF: 0.00104 AC: 10 AN: 9612

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00292 AC: 183 AN: 62688

Other (OTH) AF: 0.00106 AC: 2 AN: 1890

⚠️ 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: 0.0277 Hom.: 0

ExAC AF: 0.101 AC: 12269

ClinVar

ClinVar submissions as Germline

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_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	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; COSMIC: COSV63515828;