Genetic Variant NM_006826.4:c.464T>G (chr2-9588283-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006826.4(YWHAQ):c.464T>G(p.Ile155Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I155T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

YWHAQ
NM_006826.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.39

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YWHAQ	NM_006826.4	MANE Select	c.464T>G	p.Ile155Arg	missense	Exon 4 of 6	NP_006817.1	P27348

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
YWHAQ	ENST00000238081.8	TSL:1 MANE Select	c.464T>G	p.Ile155Arg	missense	Exon 4 of 6	ENSP00000238081.3	P27348
YWHAQ	ENST00000381844.8	TSL:1	c.464T>G	p.Ile155Arg	missense	Exon 3 of 5	ENSP00000371267.4	P27348
YWHAQ	ENST00000862428.1		c.530T>G	p.Ile177Arg	missense	Exon 5 of 7	ENSP00000532487.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33030

American (AMR)

AF:

0.00

AC:

AN:

43150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

85204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111050

Other (OTH)

AF:

0.00

AC:

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.098

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

3.8

PhyloP100

7.4

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.73

MutPred

0.67

Gain of disorder (P = 0.0109)

MVP

0.75

MPC

2.1

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.86

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over