10-122406615-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001001974.4(PLEKHA1):ā€‹c.284A>Gā€‹(p.Asn95Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,422 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.000062 ( 0 hom. )

Consequence

PLEKHA1
NM_001001974.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.82
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2961105).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLEKHA1NM_001001974.4 linkuse as main transcriptc.284A>G p.Asn95Ser missense_variant 5/12 ENST00000368990.8 NP_001001974.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHA1ENST00000368990.8 linkuse as main transcriptc.284A>G p.Asn95Ser missense_variant 5/121 NM_001001974.4 ENSP00000357986 P3Q9HB21-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000716
AC:
18
AN:
251286
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461076
Hom.:
0
Cov.:
30
AF XY:
0.0000660
AC XY:
48
AN XY:
726902
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000711
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152346
Hom.:
0
Cov.:
32
AF XY:
0.0000671
AC XY:
5
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000737
Hom.:
0
Bravo
AF:
0.0000869
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2023The c.284A>G (p.N95S) alteration is located in exon 5 (coding exon 4) of the PLEKHA1 gene. This alteration results from a A to G substitution at nucleotide position 284, causing the asparagine (N) at amino acid position 95 to be replaced by a serine (S). 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
0.15
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;T;.;D;.;D
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
.;D;D;.;D;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.30
T;T;T;T;T;T
MetaSVM
Benign
-0.41
T
MutationAssessor
Uncertain
2.0
M;.;.;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.7
D;D;.;D;D;D
REVEL
Uncertain
0.31
Sift
Benign
0.082
T;T;.;T;T;T
Sift4G
Benign
0.15
T;T;T;T;T;T
Polyphen
0.23
B;.;.;B;.;B
Vest4
0.63
MVP
0.79
MPC
1.0
ClinPred
0.14
T
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs138054087; hg19: chr10-124166131; API