12-19129884-A-T

Variant names:

• chr12-19129884-A-T
• rs1245176951
• NM_001256470.2:c.85A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001256470.2(PLEKHA5):​c.85A>T​(p.Ile29Phe) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I29V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLEKHA5 NM_001256470.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.85A>T	p.Ile29Phe	missense_variant	Exon 1 of 32	ENST00000429027.7	NP_001243399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.85A>T	p.Ile29Phe	missense_variant	Exon 1 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.5	H;H;H;H
PhyloP100		2.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.97, 0.99	.;.;D;D
Vest4		0.66
MutPred		0.55		Gain of catalytic residue at R25 (P = 0.0026);Gain of catalytic residue at R25 (P = 0.0026);Gain of catalytic residue at R25 (P = 0.0026);Gain of catalytic residue at R25 (P = 0.0026);
MVP		0.57
MPC		2.3
ClinPred		0.98	D
GERP RS		3.3
PromoterAI		0.013	Neutral
Varity_R		0.44
gMVP		0.80
Mutation Taster		=73/27	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

dbSNP: rs1245176951; hg19: chr12-19282818;