12-19257457-C-T

Position:

• chr12-19257457-C-T

Variant summary

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

The NM_001256470.2(PLEKHA5):​c.457C>T​(p.His153Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA5	NM_001256470.2	c.457C>T	p.His153Tyr	missense_variant	6/32	ENST00000429027.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.457C>T	p.His153Tyr	missense_variant	6/32	1	NM_001256470.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Jan 30, 2024

The c.457C>T (p.H153Y) alteration is located in exon 6 (coding exon 6) of the PLEKHA5 gene. This alteration results from a C to T substitution at nucleotide position 457, causing the histidine (H) at amino acid position 153 to be replaced by a tyrosine (Y). 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	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;T;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.026	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;T;D;D
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.60
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		0.37
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr12-19410391;