10-122413044-A-G

Variant summary

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

The NM_001001974.4(PLEKHA1):c.467A>G(p.Gln156Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHA1 NM_001001974.4 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.58

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, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA1	NM_001001974.4	c.467A>G	p.Gln156Arg	missense_variant, splice_region_variant	6/12	ENST00000368990.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.467A>G	p.Gln156Arg	missense_variant, splice_region_variant	6/12	1	NM_001001974.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458948 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725748

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PLEKHA1: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0087	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N;N;.;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.017	D;D;.;D;D
Sift4G	Benign	0.071	T;T;T;T;T
Polyphen		0.99	D;.;D;.;D
Vest4		0.86
MutPred		0.23		Gain of phosphorylation at T153 (P = 0.0934);Gain of phosphorylation at T153 (P = 0.0934);Gain of phosphorylation at T153 (P = 0.0934);Gain of phosphorylation at T153 (P = 0.0934);Gain of phosphorylation at T153 (P = 0.0934);
MVP		0.77
MPC		1.1
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.020		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: chr10-124172560;