12-15623289-TAAAAA-TAAA

Variant names:

• chr12-15623289-TAA-T
• rs35885542
• NM_004447.6:c.2226-4_2226-3delTT

Variant summary

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

The NM_004447.6(EPS8):​c.2226-4_2226-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,289,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 1 publications found

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]

EPS8 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 102

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Variant has high frequency in the SAS (0.00795) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2226-4_2226-3delTT		splice_region_variant, intron_variant	Intron 19 of 20	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2226-4_2226-3delTT		splice_region_variant, intron_variant	Intron 19 of 20	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes AF: 0.0000732 AC: 10 AN: 136536 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000524

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000645

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00849 AC: 952 AN: 112150 AF XY: 0.00841

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00912

Gnomad EAS exome AF: 0.00978

Gnomad FIN exome AF: 0.00535

Gnomad NFE exome AF: 0.00786

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00375 AC: 4329 AN: 1153382 Hom.: 0 AF XY: 0.00383 AC XY: 2208 AN XY: 576520

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

African (AFR) AF: 0.00294 AC: 79 AN: 26850

American (AMR) AF: 0.00768 AC: 206 AN: 26836

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 105 AN: 20298

East Asian (EAS) AF: 0.00338 AC: 114 AN: 33684

South Asian (SAS) AF: 0.00853 AC: 566 AN: 66324

European-Finnish (FIN) AF: 0.00449 AC: 187 AN: 41642

Middle Eastern (MID) AF: 0.00328 AC: 15 AN: 4576

European-Non Finnish (NFE) AF: 0.00325 AC: 2877 AN: 884576

Other (OTH) AF: 0.00370 AC: 180 AN: 48596

⚠️ 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 AF: 0.0000732 AC: 10 AN: 136558 Hom.: 0 Cov.: 31 AF XY: 0.0000757 AC XY: 5 AN XY: 66028

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

African (AFR) AF: 0.0000262 AC: 1 AN: 38228

American (AMR) AF: 0.00 AC: 0 AN: 13468

Ashkenazi Jewish (ASJ) AF: 0.000311 AC: 1 AN: 3218

East Asian (EAS) AF: 0.00 AC: 0 AN: 4788

South Asian (SAS) AF: 0.00 AC: 0 AN: 4188

European-Finnish (FIN) AF: 0.000524 AC: 4 AN: 7640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000645 AC: 4 AN: 62020

Other (OTH) AF: 0.00 AC: 0 AN: 1878

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35885542; hg19: chr12-15776223; COSMIC: COSV55527582;