rs104893878

chr4-89835580-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000345.4(SNCA):c.88G>C(p.Ala30Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNCA NM_000345.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.80

Genes affected

SNCA (HGNC:11138): (synuclein alpha) Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a region_of_interest 4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V-X(4) (size 47) in uniprot entity SYUA_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000345.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-89835579-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1678622.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 4-89835580-C-G is Pathogenic according to our data. Variant chr4-89835580-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14008.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-89835580-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.88G>C	p.Ala30Pro	missense_variant	2/6	ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.88G>C	p.Ala30Pro	missense_variant	2/6	1	NM_000345.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Parkinson disease 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	This sequence change is predicted to replace alanine with proline at codon 30 of the SNCA protein (p.(Ala30Pro)). The alanine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in an N-terminal domain helix. There is a small physicochemical difference between alanine and glycine. The variant is absent in a large population cohort (PM2; gnomAD v2.1 and v3.0). It has been shown to co-segregate with Parkinson disease in a single family (PP1; PMID: 11376188). Additionally, mouse models of the variant recapitulate the human Parkinson disease phenotype and brain pathology (PS3; PMID: 21559878, 31267130). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS3, PM2, PP1, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 22, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.79	T
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.;.;.
Vest4		0.87
MutPred		0.87		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.96
MPC		1.3
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.98

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: rs104893878; hg19: chr4-90756731;