rs4612730

Variant names:

• chr10-122416936-G-A
• rs4612730
• NM_001001974.4:c.612+934G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001001974.4(PLEKHA1):​c.612+934G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 153,858 control chromosomes in the GnomAD database, including 18,122 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 0.48 (17813 hom., cov: 29)
  • Exomes 𝑓: 0.49 (309 hom.)
• Consequence: PLEKHA1 NM_001001974.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.428
• Publications: 12 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]

MIR3941 (HGNC:38949): (microRNA 3941) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA1	NM_001001974.4	c.612+934G>A		intron_variant	Intron 7 of 11	ENST00000368990.8	NP_001001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.612+934G>A		intron_variant	Intron 7 of 11	1	NM_001001974.4	ENSP00000357986.3

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72057 AN: 151252 Hom.: 17791 Cov.: 29

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.470 AC: 2704 AN: 5750 AF XY: 0.467

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.489

Gnomad EAS exome AF: 0.583

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.489 AC: 1217 AN: 2488 Hom.: 309 Cov.: 0 AF XY: 0.500 AC XY: 641 AN XY: 1282

African (AFR) AF: 0.300 AC: 21 AN: 70

American (AMR) AF: 0.833 AC: 5 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.478 AC: 43 AN: 90

European-Finnish (FIN) AF: 0.602 AC: 253 AN: 420

Middle Eastern (MID) AF: 0.469 AC: 722 AN: 1538

European-Non Finnish (NFE) AF: 0.533 AC: 96 AN: 180

Other (OTH) AF: 0.417 AC: 75 AN: 180

GnomAD4 genome AF: 0.476 AC: 72118 AN: 151370 Hom.: 17813 Cov.: 29 AF XY: 0.488 AC XY: 36093 AN XY: 73914

African (AFR) AF: 0.374 AC: 15432 AN: 41282

American (AMR) AF: 0.556 AC: 8455 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1499 AN: 3464

East Asian (EAS) AF: 0.625 AC: 3135 AN: 5012

South Asian (SAS) AF: 0.560 AC: 2675 AN: 4774

European-Finnish (FIN) AF: 0.634 AC: 6645 AN: 10488

Middle Eastern (MID) AF: 0.490 AC: 142 AN: 290

European-Non Finnish (NFE) AF: 0.482 AC: 32683 AN: 67834

Other (OTH) AF: 0.464 AC: 975 AN: 2100

Alfa AF: 0.494 Hom.: 2485

Bravo AF: 0.469

Asia WGS AF: 0.577 AC: 2004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.22
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs4612730; hg19: chr10-124176452; COSMIC: COSV64569134; COSMIC: COSV64569134;