chr12-19257442-G-C

Position:

• chr12-19257442-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256470.2(PLEKHA5):​c.442G>C​(p.Ala148Pro) 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. 14/21 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: 0.843

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08177093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA5	NM_001256470.2	c.442G>C	p.Ala148Pro	missense_variant	6/32	ENST00000429027.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.442G>C	p.Ala148Pro	missense_variant	6/32	1	NM_001256470.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

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

Apr 11, 2023

The c.442G>C (p.A148P) alteration is located in exon 6 (coding exon 6) of the PLEKHA5 gene. This alteration results from a G to C substitution at nucleotide position 442, causing the alanine (A) at amino acid position 148 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	.;T;.;T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	D;D;D;D;T;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.082	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N;N;.;.;.
MutationTaster	Benign	0.71	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.32	T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.0050, 0.0080	.;B;B;.;.;.
Vest4		0.23
MutPred		0.34		Gain of catalytic residue at K150 (P = 0);Gain of catalytic residue at K150 (P = 0);Gain of catalytic residue at K150 (P = 0);.;.;.;
MVP		0.17
MPC		1.5
ClinPred		0.75	D
GERP RS		-2.6
Varity_R		0.14
gMVP		0.29

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: chr12-19410376;