8-17274746-C-T

Variant names:

• chr8-17274746-C-T
• rs373775451
• NM_152415.3:c.430C>T

Variant summary

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

The NM_152415.3(VPS37A):​c.430C>T​(p.Pro144Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P144T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS37A NM_152415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.430C>T	p.Pro144Ser	missense	Exon 5 of 12	NP_689628.2
	VPS37A	NM_001363173.2		c.430C>T	p.Pro144Ser	missense	Exon 5 of 12	NP_001350102.1
	VPS37A	NM_001363167.1		c.430C>T	p.Pro144Ser	missense	Exon 5 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.430C>T	p.Pro144Ser	missense	Exon 5 of 12	ENSP00000318629.4
	VPS37A	ENST00000521829.5	TSL:1	c.355C>T	p.Pro119Ser	missense	Exon 4 of 11	ENSP00000429680.1
	VPS37A	ENST00000967262.1		c.538C>T	p.Pro180Ser	missense	Exon 6 of 13	ENSP00000637321.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461592 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111766

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.085
Sift	Benign	0.41	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.49		Gain of phosphorylation at P144 (P = 0.0417)
MVP		0.093
MPC		0.015
ClinPred		0.29	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.54
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373775451; hg19: chr8-17132255;