rs797044948

Positions:

• chr16-46671766-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000299138.12(VPS35):​c.1463A>G​(p.Gln488Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS35 ENST00000299138.12 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VPS35. . Gene score misZ 3.5321 (greater than the threshold 3.09). Trascript score misZ 4.8931 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, hereditary late onset Parkinson disease, Parkinson disease, Parkinson disease 17.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 16-46671766-T-C is Pathogenic according to our data. Variant chr16-46671766-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208774.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.1463A>G	p.Gln488Arg	missense_variant	12/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.1376A>G	p.Gln459Arg	missense_variant	12/17		XP_011521529.1
VPS35	XM_005256045.4	c.1262A>G	p.Gln421Arg	missense_variant	10/15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.1463A>G	p.Gln488Arg	missense_variant	12/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*2133A>G		3_prime_UTR_variant, NMD_transcript_variant	12/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*1526A>G		3_prime_UTR_variant, NMD_transcript_variant	13/18			ENSP00000497702

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		Gain of phosphorylation at S489 (P = 0.1077);
MVP		0.83
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.89

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: rs797044948; hg19: chr16-46705678;