Genetic Variant PLEKHA1:p.Arg233Pro (chr10-122424215-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001001974.4(PLEKHA1):c.698G>C(p.Arg233Pro) variant causes a missense change involving the alteration of a 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. R233G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 23)

Failed GnomAD Quality Control

Consequence

PLEKHA1
NM_001001974.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.19

Publications

3 publications found

Variant links:

Genes affected

PLEKHA1 (HGNC:14335): (pleckstrin homology domain containing A1) This gene encodes a pleckstrin homology domain-containing adapter protein. The encoded protein is localized to the plasma membrane where it specifically binds phosphatidylinositol 3,4-bisphosphate. This protein may be involved in the formation of signaling complexes in the plasma membrane. Polymorphisms in this gene are associated with age-related macular degeneration. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 5.[provided by RefSeq, Sep 2010]

PLEKHA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHA1	NM_001001974.4	MANE Select	c.698G>C	p.Arg233Pro	missense	Exon 9 of 12	NP_001001974.1
PLEKHA1	NM_001377230.1		c.698G>C	p.Arg233Pro	missense	Exon 10 of 13	NP_001364159.1
PLEKHA1	NM_001377231.1		c.698G>C	p.Arg233Pro	missense	Exon 12 of 15	NP_001364160.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHA1	ENST00000368990.8	TSL:1 MANE Select	c.698G>C	p.Arg233Pro	missense	Exon 9 of 12	ENSP00000357986.3
PLEKHA1	ENST00000392799.7	TSL:1	c.698G>C	p.Arg233Pro	missense	Exon 10 of 13	ENSP00000376547.3
PLEKHA1	ENST00000433307.2	TSL:1	c.698G>C	p.Arg233Pro	missense	Exon 8 of 11	ENSP00000394416.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

123744

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000451

AC:

AN:

221678

AF XY:

0.00000830

show subpopulations

Gnomad AFR exome

AF:

0.0000653

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

123744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

57458

African (AFR)

AF:

0.00

AC:

AN:

32672

American (AMR)

AF:

0.00

AC:

AN:

9570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3282

East Asian (EAS)

AF:

0.00

AC:

AN:

4542

South Asian (SAS)

AF:

0.00

AC:

AN:

3924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

150

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62256

Other (OTH)

AF:

0.00

AC:

AN:

1664

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

PhyloP100

8.2

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.86

MutPred

0.64

Gain of methylation at K229 (P = 0.0457)

MVP

0.66

MPC

1.4

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.88

Mutation Taster

=28/72

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over