chr12-19274757-T-C

Variant names:

• chr12-19274757-T-C
• NM_001256470.2:c.1087T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001256470.2(PLEKHA5):​c.1087T>C​(p.Ser363Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHA5 NM_001256470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.193
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025358498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.1087T>C	p.Ser363Pro	missense_variant	Exon 11 of 32	ENST00000429027.7	NP_001243399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.1087T>C	p.Ser363Pro	missense_variant	Exon 11 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1069T>C (p.S357P) alteration is located in exon 10 (coding exon 10) of the PLEKHA5 gene. This alteration results from a T to C substitution at nucleotide position 1069, causing the serine (S) at amino acid position 357 to be replaced by a proline (P). 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	0.062
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.3
DANN	Benign	0.18
DEOGEN2	Benign	0.0019	.;T;T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.025	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	.;.;N;N;.;.
PhyloP100		-0.19
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.55	T;T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T
Polyphen		0.0010	.;.;B;B;.;.
Vest4		0.14
MutPred		0.34		.;.;Gain of catalytic residue at G356 (P = 0.0062);Gain of catalytic residue at G356 (P = 0.0062);.;.;
MVP		0.14
MPC		0.067
ClinPred		0.025	T
GERP RS		-11
Varity_R		0.060
gMVP		0.12
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr12-19427691;