12-15681305-GTAATAATAATAATAA-GTAATAATAATAA

Variant names:

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

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.60-6_60-4delTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,058,244 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 27)
  • Exomes 𝑓: 0.018 (2 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.19
• 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-GTAA-G is Benign according to our data. Variant chr12-15681305-GTAA-G is described in ClinVar as Benign. ClinVar VariationId is 769817.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 = 0.0025 (368/146948) while in subpopulation AFR AF = 0.00576 (230/39960). AF 95% confidence interval is 0.00515. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.60-6_60-4delTTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-6_60-4delTTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-6_60-4delTTA		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.60-6_60-4delTTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-6_60-4delTTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-6_60-4delTTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 366 AN: 146920 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00265

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00275

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.00209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00150

GnomAD2 exomes AF: 0.0106 AC: 1620 AN: 152932 AF XY: 0.0114

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0177 AC: 16106 AN: 911296 Hom.: 2 AF XY: 0.0183 AC XY: 8362 AN XY: 457826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0169 AC: 280 AN: 16546

American (AMR) AF: 0.0156 AC: 367 AN: 23572

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 425 AN: 16336

East Asian (EAS) AF: 0.0325 AC: 875 AN: 26900

South Asian (SAS) AF: 0.0136 AC: 489 AN: 36004

European-Finnish (FIN) AF: 0.0204 AC: 752 AN: 36910

Middle Eastern (MID) AF: 0.0221 AC: 61 AN: 2754

European-Non Finnish (NFE) AF: 0.0168 AC: 12032 AN: 715086

Other (OTH) AF: 0.0222 AC: 825 AN: 37188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00250 AC: 368 AN: 146948 Hom.: 1 Cov.: 27 AF XY: 0.00242 AC XY: 173 AN XY: 71474

African (AFR) AF: 0.00576 AC: 230 AN: 39960

American (AMR) AF: 0.00271 AC: 40 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3424

East Asian (EAS) AF: 0.00296 AC: 15 AN: 5072

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4636

European-Finnish (FIN) AF: 0.00209 AC: 19 AN: 9108

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

European-Non Finnish (NFE) AF: 0.000868 AC: 58 AN: 66808

Other (OTH) AF: 0.00149 AC: 3 AN: 2012

Alfa AF: 0.00889 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		3.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: COSV55537436;