12-15623289-TAAAAA-TAAAAAAA

Position:

• chr12-15623289-TAAAAA-TAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_004447.6(EPS8):​c.2226-3_2226-2insTT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,328,248 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600

Genes affected

EPS8 (HGNC:3420): (EGFR pathway substrate 8, signaling adaptor) This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000022 (3/136656) while in subpopulation AFR AF= 0.0000785 (3/38234). AF 95% confidence interval is 0.0000208. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.2226-3_2226-2insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.2226-3_2226-2insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000220 AC: 3 AN: 136634 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000786

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

GnomAD4 exome AF: 0.000620 AC: 739 AN: 1191592 Hom.: 0 Cov.: 0 AF XY: 0.000586 AC XY: 349 AN XY: 595820

Gnomad4 AFR exome AF: 0.00761

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000764

Gnomad4 EAS exome AF: 0.000488

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000278

Gnomad4 NFE exome AF: 0.000377

Gnomad4 OTH exome AF: 0.000638

GnomAD4 genome AF: 0.0000220 AC: 3 AN: 136656 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 1 AN XY: 66080

Gnomad4 AFR AF: 0.0000785

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35885542; hg19: chr12-15776223;