12-19274832-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001256470.2(PLEKHA5):c.1162A>G(p.Ser388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,196 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.011 (171 hom.)
• Consequence: PLEKHA5 NM_001256470.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.69

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030510426).
• BP6: Variant 12-19274832-A-G is Benign according to our data. Variant chr12-19274832-A-G is described in ClinVar as [Benign]. Clinvar id is 3056093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00998 (1520/152332) while in subpopulation EAS AF= 0.0507 (262/5172). AF 95% confidence interval is 0.0456. There are 27 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA5	NM_001256470.2	c.1162A>G	p.Ser388Gly	missense_variant	11/32	ENST00000429027.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.1162A>G	p.Ser388Gly	missense_variant	11/32	1	NM_001256470.2	A2

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1515 AN: 152214 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00647

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0169 AC: 4256 AN: 251330 Hom.: 67 AF XY: 0.0180 AC XY: 2445 AN XY: 135840

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.0542

Gnomad SAS exome AF: 0.0334

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0105 AC: 15376 AN: 1461864 Hom.: 171 Cov.: 33 AF XY: 0.0114 AC XY: 8310 AN XY: 727234

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.0221

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0394

Gnomad4 SAS exome AF: 0.0331

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.00998 AC: 1520 AN: 152332 Hom.: 27 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74486

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.0507

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.00648

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00982 Hom.: 37

Bravo AF: 0.0101

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.0160 AC: 1944

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PLEKHA5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.066
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.81	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.35	T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.013, 0.88	.;.;B;P;.;.
Vest4		0.34
MPC		0.11
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.086
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs77598867; hg19: chr12-19427766;