NM_001001974.4:c.699T>C

Variant names:

• chr10-122424216-T-C
• rs4405249
• NM_001001974.4:c.699T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001001974.4(PLEKHA1):​c.699T>C​(p.Arg233Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 1,575,738 control chromosomes in the GnomAD database, including 580,811 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (56648 hom., cov: 19)
  • Exomes 𝑓: 0.85 (524163 hom.)
• Consequence: PLEKHA1 NM_001001974.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57
• Publications: 31 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA1	NM_001001974.4	MANE Select	c.699T>C	p.Arg233Arg	synonymous	Exon 9 of 12	NP_001001974.1
	PLEKHA1	NM_001377230.1		c.699T>C	p.Arg233Arg	synonymous	Exon 10 of 13	NP_001364159.1
	PLEKHA1	NM_001377231.1		c.699T>C	p.Arg233Arg	synonymous	Exon 12 of 15	NP_001364160.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA1	ENST00000368990.8	TSL:1 MANE Select	c.699T>C	p.Arg233Arg	synonymous	Exon 9 of 12	ENSP00000357986.3
	PLEKHA1	ENST00000392799.7	TSL:1	c.699T>C	p.Arg233Arg	synonymous	Exon 10 of 13	ENSP00000376547.3
	PLEKHA1	ENST00000433307.2	TSL:1	c.699T>C	p.Arg233Arg	synonymous	Exon 8 of 11	ENSP00000394416.1

Frequencies

GnomAD3 genomes AF: 0.885 AC: 127162 AN: 143756 Hom.: 56600 Cov.: 19

Gnomad AFR AF: 0.965

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.869

GnomAD2 exomes AF: 0.882 AC: 195327 AN: 221372 AF XY: 0.880

Gnomad AFR exome AF: 0.969

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.866

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.842

Gnomad NFE exome AF: 0.838

Gnomad OTH exome AF: 0.865

GnomAD4 exome AF: 0.854 AC: 1223521 AN: 1431898 Hom.: 524163 Cov.: 42 AF XY: 0.857 AC XY: 610162 AN XY: 712068

African (AFR) AF: 0.971 AC: 30328 AN: 31236

American (AMR) AF: 0.909 AC: 32688 AN: 35966

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 21862 AN: 25262

East Asian (EAS) AF: 1.00 AC: 39430 AN: 39436

South Asian (SAS) AF: 0.953 AC: 76007 AN: 79738

European-Finnish (FIN) AF: 0.843 AC: 44517 AN: 52794

Middle Eastern (MID) AF: 0.917 AC: 4635 AN: 5052

European-Non Finnish (NFE) AF: 0.836 AC: 922690 AN: 1103380

Other (OTH) AF: 0.870 AC: 51364 AN: 59034

GnomAD4 genome AF: 0.885 AC: 127253 AN: 143840 Hom.: 56648 Cov.: 19 AF XY: 0.887 AC XY: 61523 AN XY: 69326

African (AFR) AF: 0.965 AC: 37604 AN: 38986

American (AMR) AF: 0.883 AC: 12482 AN: 14142

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2928 AN: 3426

East Asian (EAS) AF: 0.999 AC: 4937 AN: 4940

South Asian (SAS) AF: 0.962 AC: 4254 AN: 4420

European-Finnish (FIN) AF: 0.833 AC: 6836 AN: 8208

Middle Eastern (MID) AF: 0.917 AC: 255 AN: 278

European-Non Finnish (NFE) AF: 0.833 AC: 55444 AN: 66562

Other (OTH) AF: 0.871 AC: 1723 AN: 1978

Alfa AF: 0.854 Hom.: 105616

Bravo AF: 0.895

Asia WGS AF: 0.980 AC: 3405 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.51
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs4405249; hg19: chr10-124183732; COSMIC: COSV108209180;