10-122429681-A-T

Variant names:

• chr10-122429681-A-T
• rs1045216
• NM_001001974.4:c.958A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001001974.4(PLEKHA1):​c.958A>T​(p.Thr320Ser) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLEKHA1 NM_001001974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 58 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058612466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA1	NM_001001974.4	c.958A>T	p.Thr320Ser	missense_variant	Exon 12 of 12	ENST00000368990.8	NP_001001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.958A>T	p.Thr320Ser	missense_variant	Exon 12 of 12	1	NM_001001974.4	ENSP00000357986.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.084	T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.17	.;.;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N;N
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.090	N;.;N
REVEL	Benign	0.070
Sift	Benign	0.54	T;.;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.058
MutPred		0.16		Gain of phosphorylation at T320 (P = 0.0733);Gain of phosphorylation at T320 (P = 0.0733);Gain of phosphorylation at T320 (P = 0.0733);
MVP		0.15
MPC		0.32
ClinPred		0.075	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1045216; hg19: chr10-124189197;