8-100925227-T-C

Variant names:

• chr8-100925227-T-C
• rs964917
• NM_145690.3:c.295-188A>G

Variant summary

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

The NM_145690.3(YWHAZ):​c.295-188A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 152,046 control chromosomes in the GnomAD database, including 23,671 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 0.55 (23671 hom., cov: 33)
• Consequence: YWHAZ NM_145690.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33
• Publications: 11 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAZ	NM_145690.3	c.295-188A>G		intron_variant	Intron 2 of 5	ENST00000395958.6	NP_663723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YWHAZ	ENST00000395958.6	c.295-188A>G		intron_variant	Intron 2 of 5	1	NM_145690.3	ENSP00000379288.2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84128 AN: 151928 Hom.: 23665 Cov.: 33

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.554 AC: 84172 AN: 152046 Hom.: 23671 Cov.: 33 AF XY: 0.553 AC XY: 41115 AN XY: 74330

African (AFR) AF: 0.458 AC: 19011 AN: 41466

American (AMR) AF: 0.574 AC: 8765 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2036 AN: 3466

East Asian (EAS) AF: 0.636 AC: 3294 AN: 5178

South Asian (SAS) AF: 0.679 AC: 3277 AN: 4824

European-Finnish (FIN) AF: 0.513 AC: 5417 AN: 10552

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.596 AC: 40486 AN: 67960

Other (OTH) AF: 0.561 AC: 1186 AN: 2114

Alfa AF: 0.585 Hom.: 71258

Bravo AF: 0.554

Asia WGS AF: 0.619 AC: 2154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.76
PhyloP100		-2.3
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: rs964917; hg19: chr8-101937455;