10-122424214-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001001974.4(PLEKHA1):c.697C>G(p.Arg233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHA1 NM_001001974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA1	NM_001001974.4	c.697C>G	p.Arg233Gly	missense_variant	9/12	ENST00000368990.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.697C>G	p.Arg233Gly	missense_variant	9/12	1	NM_001001974.4	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418784 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 705168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.697C>G (p.R233G) alteration is located in exon 9 (coding exon 8) of the PLEKHA1 gene. This alteration results from a C to G substitution at nucleotide position 697, causing the arginine (R) at amino acid position 233 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;D;.;D
Eigen	Benign	0.074
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N;.;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D;D;.;D;D
REVEL	Uncertain	0.29
Sift	Benign	0.15	T;T;.;T;T
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.97	D;.;D;.;D
Vest4		0.84
MutPred		0.55		Gain of catalytic residue at V234 (P = 0.0431);Gain of catalytic residue at V234 (P = 0.0431);Gain of catalytic residue at V234 (P = 0.0431);Gain of catalytic residue at V234 (P = 0.0431);Gain of catalytic residue at V234 (P = 0.0431);
MVP		0.45
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.69
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-124183730;