NM_152415.3:c.866G>A

Variant names:

• chr8-17280263-G-A
• rs376210724
• NM_152415.3:c.866G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152415.3(VPS37A):​c.866G>A​(p.Ser289Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S289R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: VPS37A NM_152415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1379183).

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.866G>A	p.Ser289Asn	missense	Exon 8 of 12	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.866G>A	p.Ser289Asn	missense	Exon 8 of 12	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.866G>A	p.Ser289Asn	missense	Exon 8 of 12	NP_001350096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.866G>A	p.Ser289Asn	missense	Exon 8 of 12	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.791G>A	p.Ser264Asn	missense	Exon 7 of 11	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.974G>A	p.Ser325Asn	missense	Exon 9 of 13	ENSP00000637321.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000602 AC: 15 AN: 249080 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460594 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 726516

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111392

Other (OTH) AF: 0.0000332 AC: 2 AN: 60328

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.25
MVP		0.20
MPC		0.014
ClinPred		0.038	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.13
gMVP		0.20
Mutation Taster		=96/4	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: rs376210724; hg19: chr8-17137772;