2-9630250-T-G

Position:

• chr2-9630250-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_006826.4(YWHAQ):​c.203A>C​(p.Lys68Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YWHAQ NM_006826.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity 1433T_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YWHAQ	NM_006826.4	c.203A>C	p.Lys68Thr	missense_variant	2/6	ENST00000238081.8	NP_006817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YWHAQ	ENST00000238081.8	c.203A>C	p.Lys68Thr	missense_variant	2/6	1	NM_006826.4	ENSP00000238081	P1
YWHAQ	ENST00000381844.8	c.203A>C	p.Lys68Thr	missense_variant	1/5	1		ENSP00000371267	P1
YWHAQ	ENST00000446619.1	c.203A>C	p.Lys68Thr	missense_variant	2/4	3		ENSP00000398990
YWHAQ	ENST00000460093.1	n.19A>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.203A>C (p.K68T) alteration is located in exon 2 (coding exon 1) of the YWHAQ gene. This alteration results from a A to C substitution at nucleotide position 203, causing the lysine (K) at amino acid position 68 to be replaced by a threonine (T). 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	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Pathogenic	3.9	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.82	P;P;.
Vest4		0.83
MutPred		0.68		Loss of ubiquitination at K68 (P = 0.0063);Loss of ubiquitination at K68 (P = 0.0063);Loss of ubiquitination at K68 (P = 0.0063);
MVP		0.71
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.66

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.

Other links and lift over

hg19: chr2-9770379;