8-100931390-A-G

Variant names:

• chr8-100931390-A-G
• rs3105452
• NM_145690.3:c.295-6351T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145690.3(YWHAZ):​c.295-6351T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,922 control chromosomes in the GnomAD database, including 17,009 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (17009 hom., cov: 31)
• Consequence: YWHAZ NM_145690.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.640
• Publications: 2 publications found

Genes affected

YWHAZ (HGNC:12855): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) 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 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. [provided by RefSeq, Oct 2008]

YWHAZ Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145690.3. 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
	YWHAZ	NM_145690.3	MANE Select	c.295-6351T>C		intron	N/A	NP_663723.1
	YWHAZ	NM_001135699.2		c.295-6351T>C		intron	N/A	NP_001129171.1
	YWHAZ	NM_001135700.2		c.295-6351T>C		intron	N/A	NP_001129172.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YWHAZ	ENST00000395958.6	TSL:1 MANE Select	c.295-6351T>C		intron	N/A	ENSP00000379288.2
	YWHAZ	ENST00000353245.7	TSL:1	c.295-6351T>C		intron	N/A	ENSP00000309503.3
	YWHAZ	ENST00000395956.7	TSL:1	c.295-6351T>C		intron	N/A	ENSP00000379286.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70541 AN: 151802 Hom.: 17014 Cov.: 31

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.478

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.464 AC: 70556 AN: 151922 Hom.: 17009 Cov.: 31 AF XY: 0.467 AC XY: 34652 AN XY: 74232

African (AFR) AF: 0.333 AC: 13808 AN: 41426

American (AMR) AF: 0.507 AC: 7745 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1844 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3204 AN: 5158

South Asian (SAS) AF: 0.630 AC: 3032 AN: 4812

European-Finnish (FIN) AF: 0.447 AC: 4710 AN: 10536

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34615 AN: 67936

Other (OTH) AF: 0.474 AC: 1000 AN: 2110

Alfa AF: 0.471 Hom.: 5971

Bravo AF: 0.463

Asia WGS AF: 0.576 AC: 2005 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs3105452; hg19: chr8-101943618;