8-17286321-G-C

Variant names:

• chr8-17286321-G-C
• rs3793427
• NM_152415.3:c.1114-26G>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 1.20
• Publications: 15 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	NM_152415.3	MANE Select	c.1114-26G>C		intron	N/A	NP_689628.2
	VPS37A	NM_001363173.2		c.1114-26G>C		intron	N/A	NP_001350102.1
	VPS37A	NM_001363167.1		c.1096-26G>C		intron	N/A	NP_001350096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.1114-26G>C		intron	N/A	ENSP00000318629.4
	VPS37A	ENST00000521829.5	TSL:1	c.1039-26G>C		intron	N/A	ENSP00000429680.1
	VPS37A	ENST00000967262.1		c.1222-26G>C		intron	N/A	ENSP00000637321.1

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

GnomAD2 exomes AF: 0.386 AC: 92382 AN: 239030 AF XY: 0.378

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 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

African (AFR) AF: 0.573 AC: 18791 AN: 32790

American (AMR) AF: 0.478 AC: 20897 AN: 43760

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9688 AN: 25890

East Asian (EAS) AF: 0.745 AC: 29152 AN: 39144

South Asian (SAS) AF: 0.468 AC: 39693 AN: 84834

European-Finnish (FIN) AF: 0.305 AC: 16132 AN: 52858

Middle Eastern (MID) AF: 0.439 AC: 2515 AN: 5724

European-Non Finnish (NFE) AF: 0.258 AC: 282790 AN: 1098038

Other (OTH) AF: 0.342 AC: 20391 AN: 59550

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

African (AFR) AF: 0.559 AC: 23186 AN: 41450

American (AMR) AF: 0.436 AC: 6651 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1286 AN: 3472

East Asian (EAS) AF: 0.717 AC: 3701 AN: 5162

South Asian (SAS) AF: 0.475 AC: 2289 AN: 4824

European-Finnish (FIN) AF: 0.316 AC: 3336 AN: 10566

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17564 AN: 67986

Other (OTH) AF: 0.402 AC: 851 AN: 2116

Alfa AF: 0.285 Hom.: 4162

Bravo AF: 0.408

Asia WGS AF: 0.599 AC: 2080 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		1.2
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: rs3793427; hg19: chr8-17143830;