12-15681305-GTAATAATAATAA-G

Variant names:

• chr12-15681305-GTAATAATAATAA-G
• rs201331879
• NM_004447.6:c.60-15_60-4delTTATTATTATTA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004447.6(EPS8):​c.60-15_60-4delTTATTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000637 in 1,083,790 control chromosomes in the GnomAD database, including 6 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.000075 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000062 (6 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 12-15681305-GTAATAATAATAA-G is Benign according to our data. Variant chr12-15681305-GTAATAATAATAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2182778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000748 (11/146964) while in subpopulation SAS AF = 0.00043 (2/4650). AF 95% confidence interval is 0.0000755. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.60-15_60-4delTTATTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-15_60-4delTTATTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-15_60-4delTTATTATTATTA		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.60-15_60-4delTTATTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-15_60-4delTTATTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-15_60-4delTTATTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.0000748 AC: 11 AN: 146964 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.000548

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000619 AC: 58 AN: 936826 Hom.: 6 AF XY: 0.0000742 AC XY: 35 AN XY: 471848

African (AFR) AF: 0.0000592 AC: 1 AN: 16896

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16938

East Asian (EAS) AF: 0.00 AC: 0 AN: 28616

South Asian (SAS) AF: 0.00104 AC: 38 AN: 36560

European-Finnish (FIN) AF: 0.000128 AC: 5 AN: 38940

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

European-Non Finnish (NFE) AF: 0.0000123 AC: 9 AN: 733248

Other (OTH) AF: 0.000130 AC: 5 AN: 38492

GnomAD4 genome AF: 0.0000748 AC: 11 AN: 146964 Hom.: 0 Cov.: 27 AF XY: 0.000112 AC XY: 8 AN XY: 71454

African (AFR) AF: 0.0000752 AC: 3 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: 0.000430 AC: 2 AN: 4650

European-Finnish (FIN) AF: 0.000548 AC: 5 AN: 9124

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

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66834

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

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions

Significance: Likely benign

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		3.2
Mutation Taster		=44/56	disease causing

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;