Genetic Variant YWHAQ:p.Ser92Tyr (chr2-9630178-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_006826.4(YWHAQ):c.275C>A(p.Ser92Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

YWHAQ
NM_006826.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.90

Variant links:

Genes affected

YWHAQ (HGNC:12854): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta) 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 and rat orthologs. This gene is upregulated in patients with amyotrophic lateral sclerosis. It contains in its 5' UTR a 6 bp tandem repeat sequence which is polymorphic, however, there is no correlation between the repeat number and the disease. [provided by RefSeq, Jul 2008]

YWHAQ links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity 1433T_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31447965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAQ	NM_006826.4 link	c.275C>A	p.Ser92Tyr	missense_variant	Exon 2 of 6	ENST00000238081.8	NP_006817.1	P27348

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
YWHAQ	ENST00000238081.8 link	c.275C>A	p.Ser92Tyr	missense_variant	Exon 2 of 6	1	NM_006826.4	ENSP00000238081.3	P27348
YWHAQ	ENST00000381844.8 link	c.275C>A	p.Ser92Tyr	missense_variant	Exon 1 of 5	1		ENSP00000371267.4	P27348
YWHAQ	ENST00000446619.1 link	c.275C>A	p.Ser92Tyr	missense_variant	Exon 2 of 4	3		ENSP00000398990.1	E9PG15
YWHAQ	ENST00000460093.1 link	n.91C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275C>A (p.S92Y) alteration is located in exon 2 (coding exon 1) of the YWHAQ gene. This alteration results from a C to A substitution at nucleotide position 275, causing the serine (S) at amino acid position 92 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.010

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.49

MutPred

0.53

Loss of disorder (P = 0.0337);Loss of disorder (P = 0.0337);Loss of disorder (P = 0.0337);

MVP

0.52

MPC

1.6

ClinPred

0.96

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.37

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over