12-15681305-GTAATAATAATAATAA-GTAATAATAATAATAATAA

Variant names:

• chr12-15681305-G-GTAA
• rs201331879
• NM_004447.6:c.60-6_60-4dupTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004447.6(EPS8):​c.60-6_60-4dupTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,080,868 control chromosomes in the GnomAD database, including 716 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (599 hom., cov: 27)
  • Exomes 𝑓: 0.017 (117 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.197
• 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-15681305-G-GTAA is Benign according to our data. Variant chr12-15681305-G-GTAA is described in ClinVar as Benign. ClinVar VariationId is 508729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.60-6_60-4dupTTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-6_60-4dupTTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-6_60-4dupTTA		splice_region intron	N/A	NP_001400761.1	Q12929-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.60-4_60-3insTTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10467 AN: 146870 Hom.: 600 Cov.: 27

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0359

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0769

GnomAD2 exomes AF: 0.0142 AC: 2173 AN: 152932 AF XY: 0.0144

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.00357

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0168 AC: 15680 AN: 933970 Hom.: 117 Cov.: 11 AF XY: 0.0173 AC XY: 8158 AN XY: 470376

African (AFR) AF: 0.0769 AC: 1292 AN: 16800

American (AMR) AF: 0.0133 AC: 322 AN: 24242

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 475 AN: 16858

East Asian (EAS) AF: 0.0210 AC: 600 AN: 28514

South Asian (SAS) AF: 0.0182 AC: 664 AN: 36520

European-Finnish (FIN) AF: 0.0258 AC: 1000 AN: 38712

Middle Eastern (MID) AF: 0.0314 AC: 89 AN: 2832

European-Non Finnish (NFE) AF: 0.0141 AC: 10299 AN: 731152

Other (OTH) AF: 0.0245 AC: 939 AN: 38340

GnomAD4 genome AF: 0.0713 AC: 10470 AN: 146898 Hom.: 599 Cov.: 27 AF XY: 0.0702 AC XY: 5016 AN XY: 71450

African (AFR) AF: 0.162 AC: 6463 AN: 39912

American (AMR) AF: 0.0502 AC: 740 AN: 14738

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 202 AN: 3422

East Asian (EAS) AF: 0.0365 AC: 185 AN: 5068

South Asian (SAS) AF: 0.0528 AC: 245 AN: 4636

European-Finnish (FIN) AF: 0.0316 AC: 288 AN: 9118

Middle Eastern (MID) AF: 0.0321 AC: 9 AN: 280

European-Non Finnish (NFE) AF: 0.0325 AC: 2173 AN: 66806

Other (OTH) AF: 0.0770 AC: 155 AN: 2012

Alfa AF: 0.0199 Hom.: 16

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs201331879; hg19: chr12-15834239;