chr12-19274682-G-C

Variant names:

• chr12-19274682-G-C
• NM_001256470.2:c.1012G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256470.2(PLEKHA5):​c.1012G>C​(p.Asp338His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PLEKHA5 NM_001256470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52
• 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: 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=0.31674898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.1012G>C	p.Asp338His	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.1012G>C	p.Asp338His	missense_variant	Exon 11 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.994G>C (p.D332H) alteration is located in exon 10 (coding exon 10) of the PLEKHA5 gene. This alteration results from a G to C substitution at nucleotide position 994, causing the aspartic acid (D) at amino acid position 332 to be replaced by a histidine (H). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T;T;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;L;L;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D;T;T;T;D;T
Sift4G	Uncertain	0.051	T;D;T;T;D;T
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.28
MutPred		0.33		.;.;Gain of MoRF binding (P = 0.0489);Gain of MoRF binding (P = 0.0489);.;.;
MVP		0.20
MPC		0.15
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.48
Mutation Taster		=71/29	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: chr12-19427616;