12-90971799-C-T

Variant names:

• chr12-90971799-C-T
• rs200473998
• NM_004950.5:c.702+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004950.5(EPYC):​c.702+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,417,984 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: EPYC NM_004950.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.21
• Publications: 0 publications found

Genes affected

EPYC (HGNC:3053): (epiphycan) Dermatan sulfate proteoglycan 3 is a member of the small leucine-rich repeat proteoglycan family. This gene is composed of seven exons. It regulates fibrillogenesis by interacting with collagen fibrils and other extracellular matrix proteins. [provided by RefSeq, Jul 2008]

EPYC Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPYC	NM_004950.5	c.702+1G>A		splice_donor_variant, intron_variant	Intron 5 of 6	ENST00000261172.8	NP_004941.2
EPYC	XM_011538008.2	c.519+1G>A		splice_donor_variant, intron_variant	Intron 4 of 5		XP_011536310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPYC	ENST00000261172.8	c.702+1G>A		splice_donor_variant, intron_variant	Intron 5 of 6	1	NM_004950.5	ENSP00000261172.3
EPYC	ENST00000551767.1	c.*1G>A		downstream_gene_variant		3		ENSP00000448272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1417984 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 704394

African (AFR) AF: 0.00 AC: 0 AN: 32214

American (AMR) AF: 0.00 AC: 0 AN: 38252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25104

East Asian (EAS) AF: 0.00 AC: 0 AN: 37712

South Asian (SAS) AF: 0.00 AC: 0 AN: 76966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00000458 AC: 5 AN: 1091938

Other (OTH) AF: 0.00 AC: 0 AN: 58188

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
GERP RS		5.1
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 1

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

Other links and lift over

dbSNP: rs200473998; hg19: chr12-91365576;