NM_152415.3:c.1145A>C

Variant names:

• chr8-17286378-A-C
• rs1554498242
• NM_152415.3:c.1145A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_152415.3(VPS37A):​c.1145A>C​(p.Lys382Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K382N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VPS37A NM_152415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-17286379-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39741.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

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.1145A>C	p.Lys382Thr	missense	Exon 11 of 12	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.1145A>C	p.Lys382Thr	missense	Exon 11 of 12	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.1127A>C	p.Lys376Thr	missense	Exon 11 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.1145A>C	p.Lys382Thr	missense	Exon 11 of 12	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.1070A>C	p.Lys357Thr	missense	Exon 10 of 11	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.1253A>C	p.Lys418Thr	missense	Exon 12 of 13	ENSP00000637321.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.75		Loss of ubiquitination at K382 (P = 0.0224)
MVP		0.73
MPC		0.11
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.63
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554498242; hg19: chr8-17143887;