rs104893877

Variant names:

• chr4-89828149-C-T
• rs104893877
• NM_000345.4:c.157G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNCA NM_000345.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.47
• Publications: 4317 publications found

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]

SNCA Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• autosomal dominant Parkinson disease 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Lewy body dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chr4-89828148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1393530.
• PP5: Variant 4-89828149-C-T is Pathogenic according to our data. Variant chr4-89828149-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	NM_000345.4	MANE Select	c.157G>A	p.Ala53Thr	missense	Exon 3 of 6	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.157G>A	p.Ala53Thr	missense	Exon 3 of 6	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.157G>A	p.Ala53Thr	missense	Exon 3 of 6	NP_001139527.1	P37840-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.157G>A	p.Ala53Thr	missense	Exon 3 of 6	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.157G>A	p.Ala53Thr	missense	Exon 3 of 6	ENSP00000378437.1	P37840-1
	SNCA	ENST00000345009.8	TSL:1	c.157G>A	p.Ala53Thr	missense	Exon 2 of 4	ENSP00000343683.4	P37840-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000216 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant Parkinson disease 1 (1)
1	-	-	Autosomal dominant Parkinson disease 4 (1)
1	-	-	Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 (1)
1	-	-	Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.93	N
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.42
MutPred		0.69		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
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs104893877; hg19: chr4-90749300;