8-100924179-C-T

Position:

• chr8-100924179-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_145690.3(YWHAZ):​c.538G>A​(p.Glu180Lys) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YWHAZ NM_145690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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 8 ACMG points.

• PM1: In a chain 14-3-3 protein zeta/delta (size 244) in uniprot entity 1433Z_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_145690.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YWHAZ	NM_145690.3	c.538G>A	p.Glu180Lys	missense_variant	4/6	ENST00000395958.6	NP_663723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YWHAZ	ENST00000395958.6	c.538G>A	p.Glu180Lys	missense_variant	4/6	1	NM_145690.3	ENSP00000379288.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
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	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;D;.;D;.;D;.;.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;H;.;.;.;H;.;H;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;.;.;.;D;.;D;D;.
Vest4		0.92
MutPred		0.87		Gain of ubiquitination at E180 (P = 0.0219);Gain of ubiquitination at E180 (P = 0.0219);Gain of ubiquitination at E180 (P = 0.0219);Gain of ubiquitination at E180 (P = 0.0219);Gain of ubiquitination at E180 (P = 0.0219);.;.;.;Gain of ubiquitination at E180 (P = 0.0219);.;Gain of ubiquitination at E180 (P = 0.0219);Gain of ubiquitination at E180 (P = 0.0219);.;
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-101936407;