chr12-15669381-T-C

Variant names:

• chr12-15669381-T-C
• rs73315036
• NM_004447.6:c.516+6A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004447.6(EPS8):​c.516+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,592,022 control chromosomes in the GnomAD database, including 1,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (590 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (606 hom.)
• Consequence: EPS8 NM_004447.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004658
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.02
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-15669381-T-C is Benign according to our data. Variant chr12-15669381-T-C is described in ClinVar as Benign. ClinVar VariationId is 508706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 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.516+6A>G		splice_region intron	N/A	NP_004438.3
	EPS8	NM_001413831.1		c.516+6A>G		splice_region intron	N/A	NP_001400760.1
	EPS8	NM_001413832.1		c.516+6A>G		splice_region 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.516+6A>G		splice_region intron	N/A	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.516+6A>G		splice_region intron	N/A	ENSP00000445985.1
	EPS8	ENST00000642939.1		c.567+6A>G		splice_region intron	N/A	ENSP00000495312.1

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7505 AN: 152168 Hom.: 590 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.0493

GnomAD2 exomes AF: 0.0150 AC: 3451 AN: 229342 AF XY: 0.0112

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00616 AC: 8868 AN: 1439736 Hom.: 606 Cov.: 31 AF XY: 0.00558 AC XY: 3988 AN XY: 715144

African (AFR) AF: 0.177 AC: 5684 AN: 32104

American (AMR) AF: 0.0152 AC: 582 AN: 38366

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 100 AN: 24862

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39490

South Asian (SAS) AF: 0.000391 AC: 32 AN: 81892

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53082

Middle Eastern (MID) AF: 0.0213 AC: 120 AN: 5638

European-Non Finnish (NFE) AF: 0.00139 AC: 1539 AN: 1104866

Other (OTH) AF: 0.0135 AC: 801 AN: 59436

GnomAD4 genome AF: 0.0494 AC: 7520 AN: 152286 Hom.: 590 Cov.: 33 AF XY: 0.0475 AC XY: 3539 AN XY: 74464

African (AFR) AF: 0.165 AC: 6844 AN: 41542

American (AMR) AF: 0.0281 AC: 430 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68028

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0240 Hom.: 180

Bravo AF: 0.0573

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	EPS8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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: rs73315036; hg19: chr12-15822315; COSMIC: COSV55533745; COSMIC: COSV55533745;