12-15681305-GTAATAATAATAATAA-GTAATAATAATAATAATAATAATAA

Variant names:

• chr12-15681305-G-GTAATAATAA
• rs201331879
• NM_004447.6:c.60-12_60-4dupTTATTATTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004447.6(EPS8):​c.60-12_60-4dupTTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,083,770 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 27)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Likely 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-GTAATAATAA is Benign according to our data. Variant chr12-15681305-G-GTAATAATAA is described in ClinVar as Likely_benign. ClinVar VariationId is 724500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00533 (784/146968) while in subpopulation AFR AF = 0.0129 (517/39952). AF 95% confidence interval is 0.012. There are 4 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.60-12_60-4dupTTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-12_60-4dupTTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-12_60-4dupTTATTATTA		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_60-3insTTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 781 AN: 146940 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00530

Gnomad SAS AF: 0.000860

Gnomad FIN AF: 0.00976

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00350

GnomAD2 exomes AF: 0.000942 AC: 144 AN: 152932 AF XY: 0.000877

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.000135

Gnomad ASJ exome AF: 0.000845

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000860 AC: 806 AN: 936802 Hom.: 1 Cov.: 11 AF XY: 0.000854 AC XY: 403 AN XY: 471830

African (AFR) AF: 0.00408 AC: 69 AN: 16892

American (AMR) AF: 0.000535 AC: 13 AN: 24296

Ashkenazi Jewish (ASJ) AF: 0.000354 AC: 6 AN: 16940

East Asian (EAS) AF: 0.00112 AC: 32 AN: 28614

South Asian (SAS) AF: 0.000246 AC: 9 AN: 36562

European-Finnish (FIN) AF: 0.00378 AC: 147 AN: 38940

Middle Eastern (MID) AF: 0.00211 AC: 6 AN: 2840

European-Non Finnish (NFE) AF: 0.000641 AC: 470 AN: 733228

Other (OTH) AF: 0.00140 AC: 54 AN: 38490

GnomAD4 genome AF: 0.00533 AC: 784 AN: 146968 Hom.: 4 Cov.: 27 AF XY: 0.00574 AC XY: 410 AN XY: 71490

African (AFR) AF: 0.0129 AC: 517 AN: 39952

American (AMR) AF: 0.00163 AC: 24 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 4 AN: 3424

East Asian (EAS) AF: 0.00532 AC: 27 AN: 5072

South Asian (SAS) AF: 0.000862 AC: 4 AN: 4638

European-Finnish (FIN) AF: 0.00976 AC: 89 AN: 9118

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.00166 AC: 111 AN: 66818

Other (OTH) AF: 0.00348 AC: 7 AN: 2010

Alfa AF: 0.000447 Hom.: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EPS8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
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: rs201331879; hg19: chr12-15834239;