8-17247340-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_152415.3(VPS37A):c.96G>C(p.Leu32=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,523,514 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L32L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: VPS37A NM_152415.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.431

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-17247340-G-C is Benign according to our data. Variant chr8-17247340-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 540285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.431 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS37A	NM_152415.3	c.96G>C	p.Leu32=	synonymous_variant	1/12	ENST00000324849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS37A	ENST00000324849.9	c.96G>C	p.Leu32=	synonymous_variant	1/12	1	NM_152415.3	P1

Frequencies

GnomAD3 genomes AF: 0.000183 AC: 27 AN: 147356 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000685

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00294

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.000413

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.000495

GnomAD3 exomes AF: 0.000508 AC: 80 AN: 157426 Hom.: 0 AF XY: 0.000534 AC XY: 45 AN XY: 84228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00286

Gnomad SAS exome AF: 0.00122

Gnomad FIN exome AF: 0.000707

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000339 AC: 466 AN: 1376056 Hom.: 4 Cov.: 31 AF XY: 0.000348 AC XY: 236 AN XY: 678692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000561

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00869

Gnomad4 SAS exome AF: 0.000995

Gnomad4 FIN exome AF: 0.000862

Gnomad4 NFE exome AF: 0.0000329

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000197 AC: 29 AN: 147458 Hom.: 0 Cov.: 31 AF XY: 0.000265 AC XY: 19 AN XY: 71672

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000684

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00295

Gnomad4 SAS AF: 0.00154

Gnomad4 FIN AF: 0.000413

Gnomad4 NFE AF: 0.0000299

Gnomad4 OTH AF: 0.000489

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 53 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

- -

VPS37A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	8.1
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs199577037; hg19: chr8-17104849;