12-15623289-TAAAAA-TAA

Variant names:

• chr12-15623289-TAAA-T
• rs35885542
• NM_004447.6:c.2226-5_2226-3delTTT

Variant summary

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

The NM_004447.6(EPS8):​c.2226-5_2226-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,194,244 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 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000098 (0 hom.)
  • Failed GnomAD Quality Control
• 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004447.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.2226-5_2226-3delTTT		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.2262-5_2262-3delTTT		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.2226-5_2226-3delTTT		splice_region intron	N/A	NP_001400761.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.2226-5_2226-3delTTT		splice_region intron	N/A	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.*1486-5_*1486-3delTTT		splice_region intron	N/A	ENSP00000445985.1
	EPS8	ENST00000642939.1		c.2277-5_2277-3delTTT		splice_region intron	N/A	ENSP00000495312.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 136624 Hom.: 0 Cov.: 31

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000401 AC: 45 AN: 112150 AF XY: 0.000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000912

Gnomad EAS exome AF: 0.000867

Gnomad FIN exome AF: 0.000341

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000980 AC: 117 AN: 1194244 Hom.: 0 AF XY: 0.0000955 AC XY: 57 AN XY: 597072

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

African (AFR) AF: 0.0000734 AC: 2 AN: 27258

American (AMR) AF: 0.000398 AC: 11 AN: 27660

Ashkenazi Jewish (ASJ) AF: 0.0000477 AC: 1 AN: 20968

East Asian (EAS) AF: 0.000172 AC: 6 AN: 34880

South Asian (SAS) AF: 0.000260 AC: 18 AN: 69260

European-Finnish (FIN) AF: 0.000209 AC: 9 AN: 43150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4686

European-Non Finnish (NFE) AF: 0.0000710 AC: 65 AN: 916106

Other (OTH) AF: 0.0000995 AC: 5 AN: 50276

⚠️ 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: AC0 AF: 0.00 AC: 0 AN: 136624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 66036

African (AFR) AF: 0.00 AC: 0 AN: 38166

American (AMR) AF: 0.00 AC: 0 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3222

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.00 AC: 0 AN: 4204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62068

Other (OTH) AF: 0.00 AC: 0 AN: 1868

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060

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: COSV55528796;