Genetic Variant PLEKHA5:p.Thr182Ala (chr12-19260955-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001256470.2(PLEKHA5):c.544A>G(p.Thr182Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000694 in 1,440,192 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: 0.0000069 ( 0 hom. )

Consequence

PLEKHA5
NM_001256470.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.24

Publications

2 publications found

Variant links:

Genes affected

PLEKHA5 (HGNC:30036): (pleckstrin homology domain containing A5) Predicted to enable phosphatidylinositol phosphate binding activity. Predicted to act upstream of or within reproductive system development. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.286649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2 link	c.544A>G	p.Thr182Ala	missense_variant	Exon 7 of 32	ENST00000429027.7	NP_001243399.1	Q9HAU0-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7 link	c.544A>G	p.Thr182Ala	missense_variant	Exon 7 of 32	1	NM_001256470.2	ENSP00000404296.2		Q9HAU0-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251080

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000694

AC:

AN:

1440192

Hom.:

Cov.:

AF XY:

0.00000698

AC XY:

AN XY:

716076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33222

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25788

East Asian (EAS)

AF:

0.00

AC:

AN:

39490

South Asian (SAS)

AF:

0.00

AC:

AN:

82942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000912

AC:

AN:

1095986

Other (OTH)

AF:

0.00

AC:

AN:

59544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.544A>G (p.T182A) alteration is located in exon 7 (coding exon 7) of the PLEKHA5 gene. This alteration results from a A to G substitution at nucleotide position 544, causing the threonine (T) at amino acid position 182 to be replaced by an alanine (A). 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

0.68

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T;.;T;.;T

Eigen

Benign

-0.016

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.36

N;N;N;.;.;.

PhyloP100

4.2

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

N;N;N;D;N;N

REVEL

Benign

0.097

Sift

Benign

0.054

T;D;D;T;T;T

Sift4G

Benign

0.21

T;T;T;T;T;T

Polyphen

0.12, 0.059

.;B;B;.;.;.

Vest4

0.33

MutPred

0.42

Gain of catalytic residue at T182 (P = 0.0013);Gain of catalytic residue at T182 (P = 0.0013);Gain of catalytic residue at T182 (P = 0.0013);.;.;.;

MVP

0.29

MPC

1.6

ClinPred

0.75

GERP RS

5.3

Varity_R

0.16

gMVP

0.40

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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12-19260955-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over