rs4612730

Positions:

• chr10-122416936-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PLEKHA1	NM_001001974.4	c.612+934G>A		intron_variant		ENST00000368990.8
MIR3941	NR_037506.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHA1	ENST00000368990.8	c.612+934G>A		intron_variant		1	NM_001001974.4	P3
MIR3941	ENST00000582572.1			upstream_gene_variant

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

GnomAD3 exomes AF: 0.470 AC: 2704 AN: 5750 Hom.: 630 AF XY: 0.467 AC XY: 1263 AN XY: 2704

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 SAS exome AF: 0.519

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

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.500

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.602

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.417

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

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.464

Alfa AF: 0.498 Hom.: 2421

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

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

Publications

LitVar

Other links and lift over

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