NM_015289.5:c.139+246T>G

Variant names:

• chr15-42199650-A-C
• rs2620381
• NM_015289.5:c.139+246T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
VPS39	NM_015289.5	c.139+246T>G		intron_variant	Intron 2 of 24	ENST00000318006.10	NP_056104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS39	ENST00000318006.10	c.139+246T>G		intron_variant	Intron 2 of 24	1	NM_015289.5	ENSP00000326534.5
VPS39	ENST00000348544.4	c.139+246T>G		intron_variant	Intron 2 of 25	1		ENSP00000335193.5
MIR627	ENST00000384979.1	n.17T>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
VPS39	ENST00000568357.1	n.293+246T>G		intron_variant	Intron 2 of 2	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

GnomAD2 exomes AF: 0.0439 AC: 2546 AN: 57944 AF XY: 0.0396

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 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

African (AFR) AF: 0.122 AC: 870 AN: 7138

American (AMR) AF: 0.157 AC: 1873 AN: 11954

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 13 AN: 10652

East Asian (EAS) AF: 0.0885 AC: 1544 AN: 17448

South Asian (SAS) AF: 0.0395 AC: 1805 AN: 45674

European-Finnish (FIN) AF: 0.00134 AC: 39 AN: 29182

Middle Eastern (MID) AF: 0.00823 AC: 25 AN: 3036

European-Non Finnish (NFE) AF: 0.00156 AC: 329 AN: 211470

Other (OTH) AF: 0.0213 AC: 405 AN: 19012

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

African (AFR) AF: 0.121 AC: 4991 AN: 41284

American (AMR) AF: 0.103 AC: 1569 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.0810 AC: 413 AN: 5096

South Asian (SAS) AF: 0.0537 AC: 256 AN: 4768

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10558

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 67810

Other (OTH) AF: 0.0400 AC: 84 AN: 2102

Alfa AF: 0.0233 Hom.: 47

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
PhyloP100		-0.21
Mutation Taster		=100/0	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: rs2620381; hg19: chr15-42491848;