NM_004447.6:c.2226-6_2226-3dupTTTT

Variant names:

• chr12-15623289-T-TAAAA
• rs35885542
• NM_004447.6:c.2226-6_2226-3dupTTTT

Variant summary

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

The NM_004447.6(EPS8):​c.2226-6_2226-3dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,197,220 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 0 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: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2226-6_2226-3dupTTTT		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.2226-3_2226-2insTTTT		splice_region_variant, intron_variant	Intron 19 of 20	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000251 AC: 3 AN: 1197220 Hom.: 0 Cov.: 0 AF XY: 0.00000167 AC XY: 1 AN XY: 598526

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

African (AFR) AF: 0.0000733 AC: 2 AN: 27302

American (AMR) AF: 0.00 AC: 0 AN: 27760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21022

East Asian (EAS) AF: 0.00 AC: 0 AN: 34950

South Asian (SAS) AF: 0.00 AC: 0 AN: 69476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4688

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 918400

Other (OTH) AF: 0.00 AC: 0 AN: 50376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000359607), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060

Splicing

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

Other links and lift over

dbSNP: rs35885542; hg19: chr12-15776223;