rs1045216

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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: 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
• 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA1	NM_001001974.4	MANE Select	c.958A>G	p.Thr320Ala	missense	Exon 12 of 12	NP_001001974.1	Q9HB21-1
	PLEKHA1	NM_001377230.1		c.958A>G	p.Thr320Ala	missense	Exon 13 of 13	NP_001364159.1	Q9HB21-1
	PLEKHA1	NM_001377231.1		c.958A>G	p.Thr320Ala	missense	Exon 15 of 15	NP_001364160.1	Q9HB21-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA1	ENST00000368990.8	TSL:1 MANE Select	c.958A>G	p.Thr320Ala	missense	Exon 12 of 12	ENSP00000357986.3	Q9HB21-1
	PLEKHA1	ENST00000392799.7	TSL:1	c.958A>G	p.Thr320Ala	missense	Exon 13 of 13	ENSP00000376547.3	Q9HB21-1
	PLEKHA1	ENST00000433307.2	TSL:1	c.958A>G	p.Thr320Ala	missense	Exon 11 of 11	ENSP00000394416.1	Q9HB21-1

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

GnomAD2 exomes AF: 0.681 AC: 171087 AN: 251314 AF XY: 0.674

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 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

African (AFR) AF: 0.806 AC: 26984 AN: 33480

American (AMR) AF: 0.773 AC: 34548 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15692 AN: 26136

East Asian (EAS) AF: 0.795 AC: 31565 AN: 39694

South Asian (SAS) AF: 0.721 AC: 62181 AN: 86256

European-Finnish (FIN) AF: 0.712 AC: 38049 AN: 53414

Middle Eastern (MID) AF: 0.655 AC: 3777 AN: 5768

European-Non Finnish (NFE) AF: 0.594 AC: 660311 AN: 1111960

Other (OTH) AF: 0.640 AC: 38655 AN: 60392

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

African (AFR) AF: 0.798 AC: 33039 AN: 41416

American (AMR) AF: 0.705 AC: 10756 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2079 AN: 3466

East Asian (EAS) AF: 0.801 AC: 4142 AN: 5170

South Asian (SAS) AF: 0.727 AC: 3489 AN: 4802

European-Finnish (FIN) AF: 0.706 AC: 7440 AN: 10534

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40987 AN: 67942

Other (OTH) AF: 0.655 AC: 1383 AN: 2110

Alfa AF: 0.644 Hom.: 70371

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 v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.075
Sift	Benign	0.79	T
Sift4G	Benign	0.78	T
Polyphen		0.0	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
Mutation Taster		=64/36	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; COSMIC: COSV64569913; COSMIC: COSV64569913;