chr8-100924013-CTTAATGTA-TACAAAGCGTGCTGTCTTTGTATGAACTCT

Position:

• chr8-100924013-CTTAATGTA-TACAAAGCGTGCTGTCTTTGTATGAACTCT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP2 PP3

The NM_145690.3(YWHAZ):​c.612_620delTACATTAAGinsAGAGTTCATACAAAGACAGCACGCTTTGTA​(p.Asp204_Ser207delinsGluGluPheIleGlnArgGlnHisAlaLeuTyr) variant causes a missense, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YWHAZ NM_145690.3 missense, disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 (HGNC:):

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
• PM4: Nonframeshift variant in NON repetitive region in NM_145690.3.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YWHAZ	NM_145690.3	c.612_620delTACATTAAGinsAGAGTTCATACAAAGACAGCACGCTTTGTA	p.Asp204_Ser207delinsGluGluPheIleGlnArgGlnHisAlaLeuTyr	missense_variant, disruptive_inframe_insertion		ENST00000395958.6	NP_663723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YWHAZ	ENST00000395958.6	c.612_620delTACATTAAGinsAGAGTTCATACAAAGACAGCACGCTTTGTA	p.Asp204_Ser207delinsGluGluPheIleGlnArgGlnHisAlaLeuTyr	missense_variant, disruptive_inframe_insertion		1	NM_145690.3	ENSP00000379288.2

Frequencies

GnomAD3 genomes Cov.: 32

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

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

Feb 23, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 4 amino acids and insertion of 11 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr8-101936241;