12-15681305-GTAATAATAATAATAA-GTAATAATAA

Variant names:

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

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.60-9_60-4delTTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,082,266 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (23 hom., cov: 27)
  • Exomes 𝑓: 0.00092 (3 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-GTAATAA-G is Benign according to our data. Variant chr12-15681305-GTAATAA-G is described in ClinVar as Benign. ClinVar VariationId is 585852.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 = 0.00887 (1304/146980) while in subpopulation AFR AF = 0.0306 (1223/39954). AF 95% confidence interval is 0.0292. There are 23 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.60-9_60-4delTTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-9_60-4delTTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-9_60-4delTTATTA		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.60-9_60-4delTTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-9_60-4delTTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-9_60-4delTTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1297 AN: 146952 Hom.: 23 Cov.: 27

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.000982

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.000438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000389

Gnomad OTH AF: 0.00300

GnomAD2 exomes AF: 0.000850 AC: 130 AN: 152932 AF XY: 0.000620

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000644

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000920 AC: 860 AN: 935286 Hom.: 3 AF XY: 0.000877 AC XY: 413 AN XY: 471044

African (AFR) AF: 0.0252 AC: 425 AN: 16870

American (AMR) AF: 0.000948 AC: 23 AN: 24270

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 30 AN: 16906

East Asian (EAS) AF: 0.000632 AC: 18 AN: 28480

South Asian (SAS) AF: 0.000329 AC: 12 AN: 36512

European-Finnish (FIN) AF: 0.000309 AC: 12 AN: 38870

Middle Eastern (MID) AF: 0.00141 AC: 4 AN: 2836

European-Non Finnish (NFE) AF: 0.000388 AC: 284 AN: 732138

Other (OTH) AF: 0.00135 AC: 52 AN: 38404

GnomAD4 genome AF: 0.00887 AC: 1304 AN: 146980 Hom.: 23 Cov.: 27 AF XY: 0.00857 AC XY: 613 AN XY: 71498

African (AFR) AF: 0.0306 AC: 1223 AN: 39954

American (AMR) AF: 0.00224 AC: 33 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3424

East Asian (EAS) AF: 0.000986 AC: 5 AN: 5072

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4638

European-Finnish (FIN) AF: 0.000438 AC: 4 AN: 9122

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

European-Non Finnish (NFE) AF: 0.000389 AC: 26 AN: 66822

Other (OTH) AF: 0.00298 AC: 6 AN: 2012

Alfa AF: 0.000849 Hom.: 16

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=95/5	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;