12-15681305-G-GTAATAATAATAATAATAA

Variant names:

• chr12-15681305-G-GTAATAATAATAATAATAA
• rs201331879
• NM_004447.6:c.60-21_60-4dupTTATTATTATTATTATTA

Variant summary

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

The NM_004447.6(EPS8):​c.60-21_60-4dupTTATTATTATTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,083,824 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000225 (33/146964) while in subpopulation AFR AF = 0.000827 (33/39894). AF 95% confidence interval is 0.000605. There are 1 homozygotes in GnomAd4. There are 15 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.60-21_60-4dupTTATTATTATTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-21_60-4dupTTATTATTATTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-21_60-4dupTTATTATTATTATTATTA		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_60-3insTTATTATTATTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTATTATTATTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTATTATTATTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 33 AN: 146964 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000827

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

GnomAD4 exome AF: 0.00000213 AC: 2 AN: 936860 Hom.: 0 Cov.: 11 AF XY: 0.00000212 AC XY: 1 AN XY: 471864

African (AFR) AF: 0.000118 AC: 2 AN: 16896

American (AMR) AF: 0.00 AC: 0 AN: 24296

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 733272

Other (OTH) AF: 0.00 AC: 0 AN: 38492

GnomAD4 genome AF: 0.000225 AC: 33 AN: 146964 Hom.: 1 Cov.: 27 AF XY: 0.000210 AC XY: 15 AN XY: 71454

African (AFR) AF: 0.000827 AC: 33 AN: 39894

American (AMR) AF: 0.00 AC: 0 AN: 14734

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4650

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66834

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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

Other links and lift over

dbSNP: rs201331879; hg19: chr12-15834239;