chr8-100924283-G-A

Position:

• chr8-100924283-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_145690.3(YWHAZ):​c.434C>T​(p.Ser145Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YWHAZ NM_145690.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain 14-3-3 protein zeta/delta (size 244) in uniprot entity 1433Z_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_145690.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YWHAZ. . Gene score misZ 3.0961 (greater than the threshold 3.09). Trascript score misZ 4.4099 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YWHAZ	NM_145690.3	c.434C>T	p.Ser145Leu	missense_variant	4/6	ENST00000395958.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YWHAZ	ENST00000395958.6	c.434C>T	p.Ser145Leu	missense_variant	4/6	1	NM_145690.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T;T;T;T;.;T;T;T;T;T;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;D;.;D;.;D;.;.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H;.;.;.;H;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;.;.;.;D;.;D;D;.
Vest4		0.83
MutPred		0.78		Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);.;.;.;Loss of disorder (P = 0.0072);.;Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);.;
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754522887; hg19: chr8-101936511;