rs1554616628

Positions:

• chr7-76329927-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_012479.4(YWHAG):​c.394C>T​(p.Arg132Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YWHAG NM_012479.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.96

Genes affected

YWHAG (HGNC:12852): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma) 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 100% identical to the rat ortholog. It is induced by growth factors in human vascular smooth muscle cells, and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a site Interaction with phosphoserine on interacting protein (size 0) in uniprot entity 1433G_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YWHAG. . Gene score misZ 2.9513 (greater than the threshold 3.09). Trascript score misZ 3.8136 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 56.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-76329927-G-A is Pathogenic according to our data. Variant chr7-76329927-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76329927-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YWHAG	NM_012479.4	c.394C>T	p.Arg132Cys	missense_variant	2/2	ENST00000307630.5	NP_036611.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YWHAG	ENST00000307630.5	c.394C>T	p.Arg132Cys	missense_variant	2/2	1	NM_012479.4	ENSP00000306330.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 56 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	May 06, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Epileptic encephalopathy, early infantile, 56, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28777935). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:28777935). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PMID:28777935) (http://www.uniprot.org/uniprot/P61981#showFeaturesTable). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the YWHAG protein (p.Arg132Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of YWHAG-related conditions (PMID: 28777935, 31926053). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 438804). 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 YWHAG protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Mar 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	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; This variant is associated with the following publications: (PMID: 33767733, 28777935, 28135719, 31164858, 33393734, 31926053, 33349918, 32725632, 31785789, 36243722, 35888005, 34915349, 33619735) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.394C>T (p.R132C) alteration is located in exon 2 (coding exon 2) of the YWHAG gene. This alteration results from a C to T substitution at nucleotide position 394, causing the arginine (R) at amino acid position 132 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in multiple individuals with features consistent with YWHAG-related developmental and epileptic encephalopathy (Deciphering Developmental Disorders, 2017; Guella, 2017; Kanani, 2020; Cetica, 2024). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

YWHAG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2023

The YWHAG c.394C>T variant is predicted to result in the amino acid substitution p.Arg132Cys. This variant has been documented as a recurrent de novo variant in multiple individuals with early onset epileptic encephalopathy (See for example - Guella et al. 2017. PubMed ID: 28777935; Demos et al. 2019. PubMed ID: 31164858; Kanani et al. 2020. PubMed ID: 31926053). Additionally, a different missense variant affecting this amino acid (p.Arg132His) has been documented to be pathogenic (Brunet et al. 2021. PubMed ID: 33619735). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Loss of MoRF binding (P = 0.0083);
MVP		0.92
MPC		3.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554616628; hg19: chr7-75959244;