chr12-15623282-A-G

Variant names:

• chr12-15623282-A-G
• rs1449948926
• NM_004447.6:c.2231T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BS1_Supporting

The NM_004447.6(EPS8):​c.2231T>C​(p.Val744Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V744I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000014 (2/1432364) while in subpopulation AFR AF = 0.0000639 (2/31300). AF 95% confidence interval is 0.0000106. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2231T>C	p.Val744Ala	missense	Exon 20 of 21	NP_004438.3
	EPS8	NM_001413831.1		c.2267T>C	p.Val756Ala	missense	Exon 21 of 22	NP_001400760.1
	EPS8	NM_001413832.1		c.2231T>C	p.Val744Ala	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.2231T>C	p.Val744Ala	missense	Exon 20 of 21	ENSP00000281172.5	Q12929-1
	EPS8	ENST00000543468.5	TSL:1	n.*1491T>C		non_coding_transcript_exon	Exon 19 of 20	ENSP00000445985.1	F5H0R8
	EPS8	ENST00000543468.5	TSL:1	n.*1491T>C		3_prime_UTR	Exon 19 of 20	ENSP00000445985.1	F5H0R8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432364 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712310

African (AFR) AF: 0.0000639 AC: 2 AN: 31300

American (AMR) AF: 0.00 AC: 0 AN: 36896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 80390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102616

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.038	D
Sift4G	Benign	0.065	T
Polyphen		0.36	B
Vest4		0.61
MutPred		0.68		Loss of helix (P = 0.2022)
MVP		0.69
MPC		0.32
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.29
gMVP		0.63
Mutation Taster		=23/77	disease causing

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: rs1449948926; hg19: chr12-15776216;