chr12-19130115-C-T

Variant names:

• chr12-19130115-C-T
• rs374080735
• NM_001256470.2:c.154C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001256470.2(PLEKHA5):​c.154C>T​(p.Arg52Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,579,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PLEKHA5 NM_001256470.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.585
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16403571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.154C>T	p.Arg52Trp	missense_variant	Exon 2 of 32	ENST00000429027.7	NP_001243399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.154C>T	p.Arg52Trp	missense_variant	Exon 2 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151886 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 31 AN: 190538 AF XY: 0.000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000347

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000470

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.000167 AC: 239 AN: 1427122 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 105 AN XY: 707444

African (AFR) AF: 0.0000317 AC: 1 AN: 31570

American (AMR) AF: 0.0000245 AC: 1 AN: 40754

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.00 AC: 0 AN: 81366

European-Finnish (FIN) AF: 0.000319 AC: 16 AN: 50152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.000197 AC: 216 AN: 1096044

Other (OTH) AF: 0.0000677 AC: 4 AN: 59060

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151886 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74154

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000194 AC: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154C>T (p.R52W) alteration is located in exon 2 (coding exon 2) of the PLEKHA5 gene. This alteration results from a C to T substitution at nucleotide position 154, causing the arginine (R) at amino acid position 52 to be replaced by a tryptophan (W). 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	0.70
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0047	.;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PhyloP100		0.58
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.34
MVP		0.26
MPC		1.4
ClinPred		0.18	T
GERP RS		3.6
PromoterAI		0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.71
Mutation Taster		=63/37	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: rs374080735; hg19: chr12-19283049;