rs104893877

chr4-89828149-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_000345.4(SNCA):c.157G>A(p.Ala53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNCA NM_000345.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.47

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 Likely_pathogenic. Variant got 6 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
• PP5: Variant 4-89828149-C-T is Pathogenic according to our data. Variant chr4-89828149-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14007.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-89828149-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.157G>A	p.Ala53Thr	missense_variant	3/6	ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.157G>A	p.Ala53Thr	missense_variant	3/6	1	NM_000345.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 22, 2017

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Ala53Glu) has been determined to be pathogenic (PMID: 27066564, 24746362, 25268550, 25892596). This suggests that the alanine residue is critical for SNCA protein function and that other missense substitutions at this position may also be pathogenic. This sequence change replaces alanine with threonine at codon 53 of the SNCA protein (p.Ala53Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with early-onset Parkinson's disease in multiple families (PMID: 9197268, 26799529, 27393118). In a study of 111 individuals affected with early-onset Parkinson's disease, this variant was found in 4.5% of individuals (PMID: 24313877). ClinVar contains an entry for this variant (Variation ID: 14007). Experimental studies have shown that this missense change leads to accelerated fibrilization of the SNCA protein in vitro and in vivo (PMID: 25393002, 15144854), and causes mitochondrial dysfunction in cultured neurons (PMID: 21252228). In addition, transgenic mice carrying this variant develop a severe movement disorder with features similar to Parkinson's disease (PMID: 12062037). -

Autosomal dominant Parkinson disease 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	15
Dann	Benign	0.20
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.72	T;.;.;.;.;.;D;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.93	N;N;N;N;N;N;N;.;.
MutationTaster	Benign	0.13	A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.7	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;B;B;B;B;B;B;.;.
Vest4		0.42
MutPred		0.69		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.93
MPC		0.33
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.37
gMVP		0.35

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: rs104893877; hg19: chr4-90749300;