chr12-15780257-G-A

Variant names:

• chr12-15780257-G-A
• rs4343077
• NM_004447.6:c.-22+8904C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004447.6(EPS8):​c.-22+8904C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 151,908 control chromosomes in the GnomAD database, including 38,810 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (38807 hom., cov: 30)
  • Exomes 𝑓: 0.75 (3 hom.)
• Consequence: EPS8 NM_004447.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 5 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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255565 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.-22+8904C>T		intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.-22+8904C>T		intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.-82+8904C>T		intron	N/A	NP_001400761.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.-22+8904C>T		intron	N/A	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.-22+8904C>T		intron	N/A	ENSP00000445985.1
	EPS8	ENST00000642939.1		c.-82+8904C>T		intron	N/A	ENSP00000495312.1

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102232 AN: 151782 Hom.: 38818 Cov.: 30

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.686

GnomAD4 exome AF: 0.750 AC: 6 AN: 8 Hom.: 3 AF XY: 0.500 AC XY: 2 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 6 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.673 AC: 102230 AN: 151900 Hom.: 38807 Cov.: 30 AF XY: 0.677 AC XY: 50291 AN XY: 74268

African (AFR) AF: 0.298 AC: 12323 AN: 41362

American (AMR) AF: 0.681 AC: 10382 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2651 AN: 3468

East Asian (EAS) AF: 0.861 AC: 4448 AN: 5166

South Asian (SAS) AF: 0.871 AC: 4195 AN: 4814

European-Finnish (FIN) AF: 0.829 AC: 8755 AN: 10564

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57099 AN: 67968

Other (OTH) AF: 0.688 AC: 1451 AN: 2110

Alfa AF: 0.743 Hom.: 5586

Bravo AF: 0.642

Asia WGS AF: 0.838 AC: 2915 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.73
PhyloP100		-1.5
PromoterAI		-0.0070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4343077; hg19: chr12-15933191;