chr12-15681305-G-GTAATAATAATAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004447.6(EPS8):​c.60-15_60-4dupTTATTATTATTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 146,992 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.0011 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP6: Variant 12-15681305-G-GTAATAATAATAA is Benign according to our data. Variant chr12-15681305-G-GTAATAATAATAA is described in ClinVar as Likely_benign. ClinVar VariationId is 513294.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 = 0.00112 (165/146992) while in subpopulation AFR AF = 0.0024 (96/39964). AF 95% confidence interval is 0.00201. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

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_60-4dupTTATTATTATTA		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.60-15_60-4dupTTATTATTATTA		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.60-15_60-4dupTTATTATTATTA		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_60-3insTTATTATTATTA		splice_region intron	N/A	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.60-4_60-3insTTATTATTATTA		splice_region intron	N/A	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000880409.1		c.60-4_60-3insTTATTATTATTA		splice_region intron	N/A	ENSP00000550468.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 164 AN: 146964 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000763

Gnomad OTH AF: 0.000500

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000205 AC: 192 AN: 936854 Hom.: 0 Cov.: 11 AF XY: 0.000214 AC XY: 101 AN XY: 471860

African (AFR) AF: 0.000947 AC: 16 AN: 16896

American (AMR) AF: 0.000123 AC: 3 AN: 24296

Ashkenazi Jewish (ASJ) AF: 0.0000590 AC: 1 AN: 16942

East Asian (EAS) AF: 0.0000699 AC: 2 AN: 28616

South Asian (SAS) AF: 0.0000821 AC: 3 AN: 36562

European-Finnish (FIN) AF: 0.0000514 AC: 2 AN: 38944

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

European-Non Finnish (NFE) AF: 0.000210 AC: 154 AN: 733268

Other (OTH) AF: 0.000260 AC: 10 AN: 38490

GnomAD4 genome AF: 0.00112 AC: 165 AN: 146992 Hom.: 0 Cov.: 27 AF XY: 0.000993 AC XY: 71 AN XY: 71502

African (AFR) AF: 0.00240 AC: 96 AN: 39964

American (AMR) AF: 0.00102 AC: 15 AN: 14750

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

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5072

South Asian (SAS) AF: 0.000216 AC: 1 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: 0.000763 AC: 51 AN: 66822

Other (OTH) AF: 0.000497 AC: 1 AN: 2012

Alfa AF: 0.00 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		0.20
Mutation Taster		=99/1	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;