8-100920742-G-C

Variant names:

• chr8-100920742-G-C
• rs1554612377
• NM_145690.3:c.689C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_145690.3(YWHAZ):​c.689C>G​(p.Ser230Trp) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: YWHAZ NM_145690.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:2
• Conservation: PhyloP100: 7.68
• Publications: 1 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: Likely_pathogenic. The variant received 7 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, 0.876
• PP5: Variant 8-100920742-G-C is Pathogenic according to our data. Variant chr8-100920742-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448894.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAZ	NM_145690.3	c.689C>G	p.Ser230Trp	missense_variant	Exon 6 of 6	ENST00000395958.6	NP_663723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YWHAZ	ENST00000395958.6	c.689C>G	p.Ser230Trp	missense_variant	Exon 6 of 6	1	NM_145690.3	ENSP00000379288.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:2

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GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 10-27-2017 by Lab or GTR ID 167595. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 10-27-2017 by Lab or GTR ID 167595. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 230 of the YWHAZ protein (p.Ser230Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 31024343). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 448894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt YWHAZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects YWHAZ function (PMID: 31024343). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

YWHAZ-related neurodevelopmental syndrome Pathogenic:1

Feb 20, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The YWHAZ c.689C>G (p.Ser230Trp) missense variant results in the substitution of serine at amino acid position 230 with tryptophan. This variant has been reported in a heterozygous state in a nine year old male with a clinical diagnosis of cardiofaciocutaneous syndrome. The variant occurred de novo. The individual's phenotype included short stature, global developmental delay, dysmorphic facial features, coarse, curly hair, sparse eyebrows, pulmonic stenosis, hyperkeratosis, seizures and autistic-like and self-injurious behavior (PMID: 31024343). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Ectopic expression of c.689C>G RNA in Xenopus embryos resulted in severe head and body axis malformations compared to wild type. Co-overexpression of the c.689C>G variant RNA with c-raf RNA in the same model induced elevated Erk phosphorylation compared to wild type (PMID: 31024343). This variant was identified in a de novo state. Based on the available evidence, the c.689C>G (p.Ser230Trp) variant is classified as likely pathogenic for YWHAZ-related neurodevelopmental syndrome. -

See cases Pathogenic:1

Jul 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PP3. -

Noonan-like disorder Pathogenic:1

Sep 29, 2023

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 26, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Reclassified - variant of unknown significance Uncertain:1

Dec 23, 2021

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;T;T;T;.;T;T;T;T;T;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;D;.;D;.;D;.;.;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.;.;.;H;.;H;H;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;.;.;.;D;.;D;D;.
Vest4		0.65
MutPred		0.71		Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);.;.;.;Loss of disorder (P = 5e-04);.;Loss of disorder (P = 5e-04);Loss of disorder (P = 5e-04);.;
MVP		0.82
MPC		3.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.75
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554612377; hg19: chr8-101932970;