12-15681305-GTAATAATAATAATAA-GTAATAATAATAATAATAATAA

Variant names:

• chr12-15681305-G-GTAATAA
• rs201331879
• NM_004447.6:c.60-9_60-4dupTTATTA

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.60-9_60-4dupTTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,083,108 control chromosomes in the GnomAD database, including 741 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (417 hom., cov: 27)
  • Exomes 𝑓: 0.022 (324 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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-GTAATAA is Benign according to our data. Variant chr12-15681305-G-GTAATAA is described in ClinVar as Benign. ClinVar VariationId is 517824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 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.60-9_60-4dupTTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-9_60-4dupTTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-9_60-4dupTTATTA		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_60-3insTTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.0692 AC: 10160 AN: 146876 Hom.: 416 Cov.: 27

Gnomad AFR AF: 0.0906

Gnomad AMI AF: 0.0852

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.0654

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0179 AC: 2732 AN: 152932 AF XY: 0.0175

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.00369

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0224 AC: 21012 AN: 936204 Hom.: 324 Cov.: 11 AF XY: 0.0237 AC XY: 11152 AN XY: 471520

African (AFR) AF: 0.0413 AC: 697 AN: 16864

American (AMR) AF: 0.0135 AC: 328 AN: 24282

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 733 AN: 16924

East Asian (EAS) AF: 0.0139 AC: 399 AN: 28604

South Asian (SAS) AF: 0.00739 AC: 270 AN: 36550

European-Finnish (FIN) AF: 0.0422 AC: 1641 AN: 38898

Middle Eastern (MID) AF: 0.0219 AC: 62 AN: 2836

European-Non Finnish (NFE) AF: 0.0218 AC: 15966 AN: 732790

Other (OTH) AF: 0.0238 AC: 916 AN: 38456

GnomAD4 genome AF: 0.0692 AC: 10165 AN: 146904 Hom.: 417 Cov.: 27 AF XY: 0.0694 AC XY: 4960 AN XY: 71466

African (AFR) AF: 0.0908 AC: 3623 AN: 39920

American (AMR) AF: 0.0566 AC: 835 AN: 14746

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 263 AN: 3422

East Asian (EAS) AF: 0.0365 AC: 185 AN: 5072

South Asian (SAS) AF: 0.0155 AC: 72 AN: 4638

European-Finnish (FIN) AF: 0.0713 AC: 650 AN: 9118

Middle Eastern (MID) AF: 0.0679 AC: 19 AN: 280

European-Non Finnish (NFE) AF: 0.0642 AC: 4289 AN: 66796

Other (OTH) AF: 0.0757 AC: 152 AN: 2008

Alfa AF: 0.0190 Hom.: 16

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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; COSMIC: COSV55535685;