rs1045216

Positions:

• chr10-122429681-A-G
• chr10-122429681-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001001974.4(PLEKHA1):​c.958A>G​(p.Thr320Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,732 control chromosomes in the GnomAD database, including 323,997 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (36317 hom., cov: 30)
  • Exomes 𝑓: 0.62 (287680 hom.)
• Consequence: PLEKHA1 NM_001001974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0404374E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHA1	NM_001001974.4	c.958A>G	p.Thr320Ala	missense_variant	12/12	ENST00000368990.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.958A>G	p.Thr320Ala	missense_variant	12/12	1	NM_001001974.4	P3

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104048 AN: 151792 Hom.: 36275 Cov.: 30

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.681 AC: 171087 AN: 251314 Hom.: 59095 AF XY: 0.674 AC XY: 91542 AN XY: 135824

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.782

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.799

Gnomad SAS exome AF: 0.722

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.624 AC: 911762 AN: 1461822 Hom.: 287680 Cov.: 73 AF XY: 0.626 AC XY: 454995 AN XY: 727198

Gnomad4 AFR exome AF: 0.806

Gnomad4 AMR exome AF: 0.773

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.795

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.712

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.686 AC: 104151 AN: 151910 Hom.: 36317 Cov.: 30 AF XY: 0.693 AC XY: 51412 AN XY: 74224

Gnomad4 AFR AF: 0.798

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.655

Alfa AF: 0.638 Hom.: 44709

Bravo AF: 0.691

TwinsUK AF: 0.601 AC: 2230

ALSPAC AF: 0.588 AC: 2267

ESP6500AA AF: 0.793 AC: 3495

ESP6500EA AF: 0.603 AC: 5183

ExAC AF: 0.679 AC: 82395

Asia WGS AF: 0.764 AC: 2655 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.604

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.46
DEOGEN2	Benign	0.096	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.010	N;.;N
REVEL	Benign	0.075
Sift	Benign	0.79	T;.;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.081
MPC		0.35
ClinPred		0.0042	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs1045216; hg19: chr10-124189197; COSMIC: COSV64569913; COSMIC: COSV64569913;