17-1345459-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.756C>T(p.Asp252=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,613,628 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (5 hom.)
• Consequence: YWHAE NM_006761.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.94

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 (MetaRNN=0.008711815).
• BP6: Variant 17-1345459-G-A is Benign according to our data. Variant chr17-1345459-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 702450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.94 with no splicing effect.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YWHAE	NM_006761.5	c.756C>T	p.Asp252=	synonymous_variant	6/6	ENST00000264335.13
YWHAE	NR_024058.2	n.901C>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YWHAE	ENST00000264335.13	c.756C>T	p.Asp252=	synonymous_variant	6/6	1	NM_006761.5	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000669 AC: 168 AN: 251106 Hom.: 1 AF XY: 0.000486 AC XY: 66 AN XY: 135708

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00837

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000300 AC: 438 AN: 1461610 Hom.: 5 Cov.: 31 AF XY: 0.000279 AC XY: 203 AN XY: 727124

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00977

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74314

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00811

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0142 Hom.: 239

Bravo AF: 0.000510

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

YWHAE-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	10
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0087	T
MutationTaster	Benign	1.0	D;D;D;N
Sift4G	Benign	0.10	T
Vest4		0.31
MVP		0.90
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs150837977; hg19: chr17-1248753; COSMIC: COSV105082798;