NM_004447.6:c.60-18_60-4dupTTATTATTATTATTA

Variant names:

• chr12-15681305-G-GTAATAATAATAATAA
• rs201331879
• NM_004447.6:c.60-18_60-4dupTTATTATTATTATTA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_004447.6(EPS8):​c.60-18_60-4dupTTATTATTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,083,850 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-15681305-G-GTAATAATAATAATAA is Benign according to our data. Variant chr12-15681305-G-GTAATAATAATAATAA is described in ClinVar as Likely_benign. ClinVar VariationId is 2720063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000823 (121/146990) while in subpopulation AFR AF = 0.00275 (110/39962). AF 95% confidence interval is 0.00234. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 27. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.60-18_60-4dupTTATTATTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-18_60-4dupTTATTATTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-18_60-4dupTTATTATTATTATTA		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_60-3insTTATTATTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTATTATTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTATTATTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.000810 AC: 119 AN: 146962 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000407

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: 0.0000598

Gnomad OTH AF: 0.000500

GnomAD4 exome AF: 0.0000267 AC: 25 AN: 936860 Hom.: 0 Cov.: 11 AF XY: 0.0000318 AC XY: 15 AN XY: 471864

African (AFR) AF: 0.000829 AC: 14 AN: 16896

American (AMR) AF: 0.0000412 AC: 1 AN: 24296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16942

East Asian (EAS) AF: 0.0000349 AC: 1 AN: 28616

South Asian (SAS) AF: 0.00 AC: 0 AN: 36562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2840

European-Non Finnish (NFE) AF: 0.00000682 AC: 5 AN: 733272

Other (OTH) AF: 0.000104 AC: 4 AN: 38492

GnomAD4 genome AF: 0.000823 AC: 121 AN: 146990 Hom.: 0 Cov.: 27 AF XY: 0.000811 AC XY: 58 AN XY: 71502

African (AFR) AF: 0.00275 AC: 110 AN: 39962

American (AMR) AF: 0.000407 AC: 6 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000599 AC: 4 AN: 66822

Other (OTH) AF: 0.000497 AC: 1 AN: 2012

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPS8-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=99/1	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201331879; hg19: chr12-15834239;