8-17286321-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152415.3(VPS37A):c.1114-26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,594,638 control chromosomes in the GnomAD database, including 89,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13117 hom., cov: 32)
  • Exomes 𝑓: 0.31 (76447 hom.)
• Consequence: VPS37A NM_152415.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20

Genes affected

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-17286321-G-C is Benign according to our data. Variant chr8-17286321-G-C is described in ClinVar as [Benign]. Clinvar id is 1247255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS37A	NM_152415.3	c.1114-26G>C		intron_variant		ENST00000324849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS37A	ENST00000324849.9	c.1114-26G>C		intron_variant		1	NM_152415.3	P1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59022 AN: 151932 Hom.: 13086 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.386 AC: 92382 AN: 239030 Hom.: 20175 AF XY: 0.378 AC XY: 48922 AN XY: 129258

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.705

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.305 AC: 440049 AN: 1442588 Hom.: 76447 Cov.: 27 AF XY: 0.308 AC XY: 221397 AN XY: 718032

Gnomad4 AFR exome AF: 0.573

Gnomad4 AMR exome AF: 0.478

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.745

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.305

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.389 AC: 59104 AN: 152050 Hom.: 13117 Cov.: 32 AF XY: 0.396 AC XY: 29403 AN XY: 74318

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.402

Alfa AF: 0.285 Hom.: 4162

Bravo AF: 0.408

Asia WGS AF: 0.599 AC: 2080 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	11
Dann	Benign	0.65

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: rs3793427; hg19: chr8-17143830;