Variant 22-31944744-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003405.4(YWHAH):c.11G>A(p.Arg4Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000792 in 1,262,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

YWHAH
NM_003405.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

YWHAH (HGNC:12853): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta) 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 bovine orthologs. This gene contains a 7 bp repeat sequence in its 5' UTR, and changes in the number of this repeat have been associated with early-onset schizophrenia and psychotic bipolar disorder. [provided by RefSeq, Jun 2009]

YWHAH links:

YWHAH-AS1 (HGNC:23051): (YWHAH antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

YWHAH-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
YWHAH	NM_003405.4 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	1/2	ENST00000248975.6	NP_003396.1
YWHAH-AS1	NR_126507.1 linkuse as main transcript	n.130+489C>T		intron_variant, non_coding_transcript_variant
YWHAH-AS1	NR_171018.1 linkuse as main transcript	n.134+489C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YWHAH	ENST00000248975.6 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	1/2	1	NM_003405.4	ENSP00000248975	P1
YWHAH-AS1	ENST00000484682.2 linkuse as main transcript	n.114+489C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.92e-7

AC:

AN:

1262316

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

622806

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.91e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The c.11G>A (p.R4Q) alteration is located in exon 1 (coding exon 1) of the YWHAH gene. This alteration results from a G to A substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a glutamine (Q). 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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.59

MutPred

0.60

Loss of MoRF binding (P = 0.008);Loss of MoRF binding (P = 0.008);

MVP

0.70

MPC

1.5

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.2

Varity_R

0.60

gMVP

0.59

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