17-1361136-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006761.5(YWHAE):c.534C>T(p.Ser178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,036 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: YWHAE NM_006761.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.947

Genes affected

YWHAE (HGNC:12851): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon) This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the mouse ortholog. It interacts with CDC25 phosphatases, RAF1 and IRS1 proteins, suggesting its role in diverse biochemical activities related to signal transduction, such as cell division and regulation of insulin sensitivity. It has also been implicated in the pathogenesis of small cell lung cancer. Two transcript variants, one protein-coding and the other non-protein-coding, have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-1361136-G-A is Benign according to our data. Variant chr17-1361136-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 705898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1361136-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.947 with no splicing effect.
• BS2: High AC in GnomAd at 192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YWHAE	NM_006761.5	c.534C>T	p.Ser178=	synonymous_variant	4/6	ENST00000264335.13
YWHAE	NR_024058.2	n.679C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YWHAE	ENST00000264335.13	c.534C>T	p.Ser178=	synonymous_variant	4/6	1	NM_006761.5	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00109 AC: 274 AN: 251450 Hom.: 0 AF XY: 0.00107 AC XY: 145 AN XY: 135902

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00197 AC: 2881 AN: 1461842 Hom.: 4 Cov.: 32 AF XY: 0.00198 AC XY: 1439 AN XY: 727232

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.000994 AC XY: 74 AN XY: 74418

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00118

EpiCase AF: 0.00278

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

YWHAE-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	4.3
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139215804; hg19: chr17-1264430; COSMIC: COSV51981261; COSMIC: COSV51981261;