NM_004447.6:c.2226-4_2226-3dupTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_004447.6(EPS8):​c.2226-4_2226-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 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, 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: Likely_benign. The variant received -4 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.2226-4_2226-3dupTT		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.2262-4_2262-3dupTT		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.2226-4_2226-3dupTT		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.2226-3_2226-2insTT		splice_region intron	N/A	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.*1486-3_*1486-2insTT		splice_region intron	N/A	ENSP00000445985.1
	EPS8	ENST00000642939.1		c.2277-3_2277-2insTT		splice_region intron	N/A	ENSP00000495312.1

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

GnomAD2 exomes AF: 0.00123 AC: 138 AN: 112150 AF XY: 0.00114

Gnomad AFR exome AF: 0.00483

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.000456

Gnomad EAS exome AF: 0.000991

Gnomad FIN exome AF: 0.000341

Gnomad NFE exome AF: 0.000699

Gnomad OTH exome AF: 0.00273

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

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

African (AFR) AF: 0.00761 AC: 206 AN: 27058

American (AMR) AF: 0.00116 AC: 32 AN: 27622

Ashkenazi Jewish (ASJ) AF: 0.000764 AC: 16 AN: 20948

East Asian (EAS) AF: 0.000488 AC: 17 AN: 34854

South Asian (SAS) AF: 0.00110 AC: 76 AN: 69098

European-Finnish (FIN) AF: 0.000278 AC: 12 AN: 43130

Middle Eastern (MID) AF: 0.000642 AC: 3 AN: 4670

European-Non Finnish (NFE) AF: 0.000377 AC: 345 AN: 914034

Other (OTH) AF: 0.000638 AC: 32 AN: 50178

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

African (AFR) AF: 0.0000785 AC: 3 AN: 38234

American (AMR) AF: 0.00 AC: 0 AN: 13478

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

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7676

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62060

Other (OTH) AF: 0.00 AC: 0 AN: 1880

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism

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;