rs2620381

chr15-42199650-A-C

Variant summary

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

The NM_015289.5(VPS39):c.139+246T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 507,106 control chromosomes in the GnomAD database, including 840 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 0.049 (438 hom., cov: 31)
  • Exomes 𝑓: 0.019 (402 hom.)
• Consequence: VPS39 NM_015289.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215

Genes affected

VPS39 (HGNC:20593): (VPS39 subunit of HOPS complex) This gene encodes a protein that may promote clustering and fusion of late endosomes and lysosomes. The protein may also act as an adaptor protein that modulates the transforming growth factor-beta response by coupling the transforming growth factor-beta receptor complex to the Smad pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MIR627 (HGNC:32883): (microRNA 627) 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS39	NM_015289.5	c.139+246T>G		intron_variant		ENST00000318006.10
MIR627	NR_030357.1	n.17T>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS39	ENST00000318006.10	c.139+246T>G		intron_variant		1	NM_015289.5	P4
VPS39	ENST00000348544.4	c.139+246T>G		intron_variant		1		A1
MIR627	ENST00000384979.1	n.17T>G		mature_miRNA_variant	1/1
VPS39	ENST00000568357.1	n.293+246T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7406 AN: 151424 Hom.: 437 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0810

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.0404

GnomAD3 exomes AF: 0.0439 AC: 2546 AN: 57944 Hom.: 202 AF XY: 0.0396 AC XY: 1215 AN XY: 30668

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.00156

Gnomad EAS exome AF: 0.0930

Gnomad SAS exome AF: 0.0469

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0194 AC: 6903 AN: 355566 Hom.: 402 Cov.: 4 AF XY: 0.0196 AC XY: 3885 AN XY: 197986

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0885

Gnomad4 SAS exome AF: 0.0395

Gnomad4 FIN exome AF: 0.00134

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0490 AC: 7430 AN: 151540 Hom.: 438 Cov.: 31 AF XY: 0.0496 AC XY: 3672 AN XY: 74082

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0810

Gnomad4 SAS AF: 0.0537

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.0400

Alfa AF: 0.0209 Hom.: 45

Bravo AF: 0.0620

Asia WGS AF: 0.0700 AC: 241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.1
Dann	Benign	0.74

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: rs2620381; hg19: chr15-42491848;