rs3752827

Variant names:

• chr17-1362031-T-A
• rs3752827
• NM_006761.5:c.265-23A>T

Variant summary

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

The NM_006761.5(YWHAE):​c.265-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,413,312 control chromosomes in the GnomAD database, including 85,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.36 (9941 hom., cov: 31)
  • Exomes 𝑓: 0.35 (75809 hom.)
• Consequence: YWHAE NM_006761.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.564
• Publications: 7 publications found

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]

YWHAE Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-1362031-T-A is Benign according to our data. Variant chr17-1362031-T-A is described in ClinVar as Benign. ClinVar VariationId is 260033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006761.5. 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
	YWHAE	NM_006761.5	MANE Select	c.265-23A>T		intron	N/A	NP_006752.1
	YWHAE	NR_024058.2		n.410-23A>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YWHAE	ENST00000264335.13	TSL:1 MANE Select	c.265-23A>T		intron	N/A	ENSP00000264335.8
	YWHAE	ENST00000571732.5	TSL:1	c.199-23A>T		intron	N/A	ENSP00000461762.1
	YWHAE	ENST00000575977.1	TSL:2	c.264+2828A>T		intron	N/A	ENSP00000460712.1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54044 AN: 151740 Hom.: 9916 Cov.: 31

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.384 AC: 63515 AN: 165272 AF XY: 0.377

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.601

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.348 AC: 439351 AN: 1261454 Hom.: 75809 Cov.: 19 AF XY: 0.347 AC XY: 219141 AN XY: 631374

African (AFR) AF: 0.333 AC: 8852 AN: 26570

American (AMR) AF: 0.580 AC: 15202 AN: 26210

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 7658 AN: 21966

East Asian (EAS) AF: 0.417 AC: 14867 AN: 35688

South Asian (SAS) AF: 0.331 AC: 22475 AN: 67918

European-Finnish (FIN) AF: 0.361 AC: 17901 AN: 49562

Middle Eastern (MID) AF: 0.293 AC: 1476 AN: 5040

European-Non Finnish (NFE) AF: 0.341 AC: 333213 AN: 976426

Other (OTH) AF: 0.340 AC: 17707 AN: 52074

GnomAD4 genome AF: 0.356 AC: 54123 AN: 151858 Hom.: 9941 Cov.: 31 AF XY: 0.361 AC XY: 26790 AN XY: 74204

African (AFR) AF: 0.334 AC: 13823 AN: 41400

American (AMR) AF: 0.509 AC: 7756 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1923 AN: 5172

South Asian (SAS) AF: 0.324 AC: 1559 AN: 4810

European-Finnish (FIN) AF: 0.355 AC: 3730 AN: 10514

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.337 AC: 22876 AN: 67944

Other (OTH) AF: 0.375 AC: 789 AN: 2104

Alfa AF: 0.345 Hom.: 1748

Bravo AF: 0.366

Asia WGS AF: 0.360 AC: 1253 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.012
DANN	Benign	0.32
PhyloP100		0.56
BranchPoint Hunter		1.0
Mutation Taster		=55/45	polymorphism

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: rs3752827; hg19: chr17-1265325; COSMIC: COSV51981351; COSMIC: COSV51981351;