Genetic Variant PLEKHA4:p.Arg615Gln (chr19-48841210-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020904.3(PLEKHA4):c.1844G>A(p.Arg615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,612,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R615W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PLEKHA4
NM_020904.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.926

Variant links:

Genes affected

PLEKHA4 (HGNC:14339): (pleckstrin homology domain containing A4) This gene encodes a pleckstrin homology (PH) domain-containing protein. The PH domain is found near the N-terminus and contains a putative phosphatidylinositol 3, 4, 5-triphosphate-binding motif (PPBM). Elevated expression of this gene has been observed in some melanomas. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2017]

PLEKHA4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038260907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA4	NM_020904.3 link	c.1844G>A	p.Arg615Gln	missense_variant	Exon 17 of 20	ENST00000263265.11	NP_065955.2	Q9H4M7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA4	ENST00000263265.11 link	c.1844G>A	p.Arg615Gln	missense_variant	Exon 17 of 20	1	NM_020904.3	ENSP00000263265.5		Q9H4M7-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000447

AC:

AN:

245930

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

133424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000811

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1460648

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000609

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1844G>A (p.R615Q) alteration is located in exon 17 (coding exon 16) of the PLEKHA4 gene. This alteration results from a G to A substitution at nucleotide position 1844, causing the arginine (R) at amino acid position 615 to be replaced by a glutamine (Q). 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

Benign

0.083

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.62

M_CAP

Benign

0.018

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.080

REVEL

Benign

0.017

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.028

Polyphen

0.0030

Vest4

0.24

MVP

0.26

MPC

0.25

ClinPred

0.054

GERP RS

2.1

Varity_R

0.052

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over