NM_004447.6:c.2283T>G

Variant names:

• chr12-15623230-A-C
• rs7137185
• NM_004447.6:c.2283T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004447.6(EPS8):​c.2283T>G​(p.Asp761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,613,380 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D761N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (77 hom.)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.221
• Publications: 11 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072618723).
• BP6: Variant 12-15623230-A-C is Benign according to our data. Variant chr12-15623230-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 499499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00746 (1136/152184) while in subpopulation AMR AF = 0.0143 (219/15286). AF 95% confidence interval is 0.0128. There are 5 homozygotes in GnomAd4. There are 545 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.2283T>G	p.Asp761Glu	missense	Exon 20 of 21	NP_004438.3
	EPS8	NM_001413831.1		c.2319T>G	p.Asp773Glu	missense	Exon 21 of 22	NP_001400760.1
	EPS8	NM_001413832.1		c.2283T>G	p.Asp761Glu	missense	Exon 21 of 22	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.2283T>G	p.Asp761Glu	missense	Exon 20 of 21	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.*1543T>G		non_coding_transcript_exon	Exon 19 of 20	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000543468.5	TSL:1	n.*1543T>G		3_prime_UTR	Exon 19 of 20	ENSP00000445985.1	F5H0R8

Frequencies

GnomAD3 genomes AF: 0.00746 AC: 1134 AN: 152070 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00721 AC: 1809 AN: 251016 AF XY: 0.00748

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00530

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00880

Gnomad OTH exome AF: 0.00997

GnomAD4 exome AF: 0.00799 AC: 11678 AN: 1461196 Hom.: 77 Cov.: 30 AF XY: 0.00805 AC XY: 5853 AN XY: 726920

African (AFR) AF: 0.00102 AC: 34 AN: 33452

American (AMR) AF: 0.00604 AC: 270 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 678 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00769 AC: 663 AN: 86194

European-Finnish (FIN) AF: 0.00219 AC: 117 AN: 53412

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5762

European-Non Finnish (NFE) AF: 0.00838 AC: 9315 AN: 1111512

Other (OTH) AF: 0.00863 AC: 521 AN: 60370

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152184 Hom.: 5 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74424

African (AFR) AF: 0.00120 AC: 50 AN: 41524

American (AMR) AF: 0.0143 AC: 219 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4812

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 67994

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00942 Hom.: 39

Bravo AF: 0.00793

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00736 AC: 893

Asia WGS AF: 0.00260 AC: 11 AN: 3478

EpiCase AF: 0.00993

EpiControl AF: 0.00914

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.9
DANN	Benign	0.85
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.22
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.15
Sift	Benign	0.99	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.18		Gain of ubiquitination at K760 (P = 0.0945)
MVP		0.31
MPC		0.11
ClinPred		0.0059	T
GERP RS		1.9
Varity_R		0.042
gMVP		0.24
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7137185; hg19: chr12-15776164; COSMIC: COSV107261780;