8-17247340-G-C

Variant names:

• chr8-17247340-G-C
• rs199577037
• NM_152415.3:c.96G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_152415.3(VPS37A):​c.96G>C​(p.Leu32Leu) 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, single submitter B:2
• Conservation: PhyloP100: 0.431
• Publications: 0 publications found

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]

VPS37A Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 53

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000301184 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 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 VariationId is 540285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.431 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152415.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	NM_152415.3	MANE Select	c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 12	NP_689628.2
	VPS37A	NM_001363173.2		c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 12	NP_001350102.1
	VPS37A	NM_001363167.1		c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 12	NP_001350096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 12	ENSP00000318629.4
	VPS37A	ENST00000521829.5	TSL:1	c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 11	ENSP00000429680.1
	VPS37A	ENST00000518038.1	TSL:3	c.96G>C	p.Leu32Leu	synonymous	Exon 1 of 3	ENSP00000430456.1

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

GnomAD2 exomes AF: 0.000508 AC: 80 AN: 157426 AF XY: 0.000534

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31114

American (AMR) AF: 0.0000561 AC: 2 AN: 35640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24288

East Asian (EAS) AF: 0.00869 AC: 294 AN: 33846

South Asian (SAS) AF: 0.000995 AC: 79 AN: 79374

European-Finnish (FIN) AF: 0.000862 AC: 40 AN: 46386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 0.0000329 AC: 35 AN: 1063896

Other (OTH) AF: 0.000284 AC: 16 AN: 56322

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

African (AFR) AF: 0.00 AC: 0 AN: 40238

American (AMR) AF: 0.0000684 AC: 1 AN: 14614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00295 AC: 14 AN: 4750

South Asian (SAS) AF: 0.00154 AC: 7 AN: 4548

European-Finnish (FIN) AF: 0.000413 AC: 4 AN: 9674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000299 AC: 2 AN: 66996

Other (OTH) AF: 0.000489 AC: 1 AN: 2044

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 53 (1)
-	-	1	VPS37A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		0.43
PromoterAI		-0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs199577037; hg19: chr8-17104849;