12-19274579-A-G

Variant names:

• chr12-19274579-A-G
• rs61755451
• NM_001256470.2:c.909A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001256470.2(PLEKHA5):​c.909A>G​(p.Arg303Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,522 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (120 hom.)
• Consequence: PLEKHA5 NM_001256470.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.68
• Publications: 2 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-19274579-A-G is Benign according to our data. Variant chr12-19274579-A-G is described in ClinVar as [Benign]. Clinvar id is 781698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.909A>G	p.Arg303Arg	synonymous_variant	Exon 11 of 32	ENST00000429027.7	NP_001243399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.909A>G	p.Arg303Arg	synonymous_variant	Exon 11 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152204 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00736 AC: 1846 AN: 250786 AF XY: 0.00789

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00548

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00769

GnomAD4 exome AF: 0.0121 AC: 17661 AN: 1461200 Hom.: 120 Cov.: 31 AF XY: 0.0120 AC XY: 8700 AN XY: 726968

African (AFR) AF: 0.00204 AC: 68 AN: 33404

American (AMR) AF: 0.00535 AC: 239 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00714 AC: 616 AN: 86240

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53354

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.0143 AC: 15947 AN: 1111588

Other (OTH) AF: 0.0104 AC: 626 AN: 60360

GnomAD4 genome AF: 0.00812 AC: 1237 AN: 152322 Hom.: 6 Cov.: 32 AF XY: 0.00773 AC XY: 576 AN XY: 74480

African (AFR) AF: 0.00255 AC: 106 AN: 41570

American (AMR) AF: 0.00987 AC: 151 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00457 AC: 22 AN: 4818

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 909 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0111 Hom.: 18

Bravo AF: 0.00806

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PLEKHA5-related disorder Benign:1

Mar 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		1.7
Mutation Taster		=100/0	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: rs61755451; hg19: chr12-19427513;