rs541623528

chr8-17280148-A-Cchr8-17280148-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152415.3(VPS37A):c.834A>C(p.Glu278Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E278E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS37A NM_152415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16232726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS37A	NM_152415.3	c.834A>C	p.Glu278Asp	missense_variant	7/12	ENST00000324849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS37A	ENST00000324849.9	c.834A>C	p.Glu278Asp	missense_variant	7/12	1	NM_152415.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.080	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.52	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.33
MutPred		0.44		Loss of disorder (P = 0.1551);.;.;
MVP		0.24
MPC		0.015
ClinPred		0.31	T
GERP RS		0.70
Varity_R		0.16
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs541623528; hg19: chr8-17137657;