15-61854545-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020821.3(VPS13C):c.11174C>A(p.Ala3725Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS13C NM_020821.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

Genes affected

VPS13C (HGNC:23594): (vacuolar protein sorting 13 homolog C) Involved in mitochondrion organization and negative regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization. Located in cytosol and mitochondrial outer membrane. Implicated in Parkinson's disease 23. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27473864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13C	NM_020821.3	c.11174C>A	p.Ala3725Asp	missense_variant	85/85	ENST00000644861.2
LOC124903501	XR_007064668.1	n.159+5073G>T		intron_variant, non_coding_transcript_variant
VPS13C	NM_017684.5	c.11045C>A	p.Ala3682Asp	missense_variant	83/83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13C	ENST00000644861.2	c.11174C>A	p.Ala3725Asp	missense_variant	85/85		NM_020821.3	P3
	ENST00000642740.1	n.172+5073G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2021

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3725 of the VPS13C protein (p.Ala3725Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VPS13C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Polyphen		0.51	P;D;P
Vest4		0.67, 0.71
MutPred		0.35		Loss of loop (P = 9e-04);.;Loss of loop (P = 9e-04);
MVP		0.84
MPC		0.21
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.30
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-62146744;