12-15681305-GTAATAATAATAATAA-GTAATAA

Variant names:

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

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_60-4delTTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,083,710 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-GTAATAATAA-G is Benign according to our data. Variant chr12-15681305-GTAATAATAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1218122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000313 (46/146990) while in subpopulation NFE AF = 0.000464 (31/66822). AF 95% confidence interval is 0.000335. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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_60-4delTTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-12_60-4delTTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-12_60-4delTTATTATTA		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.60-12_60-4delTTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-12_60-4delTTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-12_60-4delTTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 46 AN: 146964 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

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: 0.000464

Gnomad OTH AF: 0.00150

GnomAD2 exomes AF: 0.000288 AC: 44 AN: 152932 AF XY: 0.000211

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000591

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000348 AC: 326 AN: 936720 Hom.: 5 AF XY: 0.000324 AC XY: 153 AN XY: 471798

African (AFR) AF: 0.000355 AC: 6 AN: 16892

American (AMR) AF: 0.000329 AC: 8 AN: 24294

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

East Asian (EAS) AF: 0.000105 AC: 3 AN: 28606

South Asian (SAS) AF: 0.000246 AC: 9 AN: 36558

European-Finnish (FIN) AF: 0.000128 AC: 5 AN: 38930

Middle Eastern (MID) AF: 0.000352 AC: 1 AN: 2840

European-Non Finnish (NFE) AF: 0.000376 AC: 276 AN: 733174

Other (OTH) AF: 0.000468 AC: 18 AN: 38484

GnomAD4 genome AF: 0.000313 AC: 46 AN: 146990 Hom.: 0 Cov.: 27 AF XY: 0.000308 AC XY: 22 AN XY: 71500

African (AFR) AF: 0.000225 AC: 9 AN: 39962

American (AMR) AF: 0.000203 AC: 3 AN: 14750

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4638

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

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

European-Non Finnish (NFE) AF: 0.000464 AC: 31 AN: 66822

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

Alfa AF: 0.000179 Hom.: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
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;