NM_152415.3:c.430C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS37A	NM_152415.3	c.430C>T	p.Pro144Ser	missense_variant	Exon 5 of 12	ENST00000324849.9	NP_689628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS37A	ENST00000324849.9	c.430C>T	p.Pro144Ser	missense_variant	Exon 5 of 12	1	NM_152415.3	ENSP00000318629.4
VPS37A	ENST00000521829.5	c.355C>T	p.Pro119Ser	missense_variant	Exon 4 of 11	1		ENSP00000429680.1
VPS37A	ENST00000520140.5	n.430C>T		non_coding_transcript_exon_variant	Exon 5 of 12	5		ENSP00000428823.1
VPS37A	ENST00000425020.6	n.488-30C>T		intron_variant	Intron 5 of 11	2		ENSP00000412824.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.085
Sift	Benign	0.41	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0020	B;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-17132255;