NM_012479.4:c.387C>G

Variant names:

• chr7-76329934-G-C
• rs1554616630
• NM_012479.4:c.387C>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_012479.4(YWHAG):​c.387C>G​(p.Asp129Glu) variant causes a missense change. 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 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:3
• Conservation: PhyloP100: 6.91
• Publications: 1 publications found

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]

YWHAG Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 56

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.9513 (below the threshold of 3.09). Trascript score misZ: 3.8136 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 56, undetermined early-onset epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-76329934-G-C is Pathogenic according to our data. Variant chr7-76329934-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAG	NM_012479.4	c.387C>G	p.Asp129Glu	missense_variant	Exon 2 of 2	ENST00000307630.5	NP_036611.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YWHAG	ENST00000307630.5	c.387C>G	p.Asp129Glu	missense_variant	Exon 2 of 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 56 Pathogenic:2

Sep 12, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Epileptic encephalopathy, early infantile, 56, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28777935). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. 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). -

not provided Pathogenic:1

Oct 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Lennox-Gastaut syndrome (PMID: 23934111, 28777935). In at least one individual the variant was observed to be de novo. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 129 of the YWHAG protein (p.Asp129Glu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 438806). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Gain of ubiquitination at K127 (P = 0.0641);
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.84
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554616630; hg19: chr7-75959251;