chr4-89828149-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• 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 12 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.157G>A	p.Ala53Thr	missense_variant	Exon 3 of 6	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.157G>A	p.Ala53Thr	missense_variant	Exon 3 of 6	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000216 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 22, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24450731, 25657004, 25383638, 26201615, 14550771, 22764233, 22399753, 23560093, 20544898, 20041693, 22067166, 12239163, 18808659, 21700325, 24728187, 20340137, 20148295, 12716427, 22090514, 20334438, 21721555, 19126542, 20592036, 21252228, 21795716, 25635052, 21718702, 15033366, 19548659, 21693148, 21684335, 21658409, 25665531, 27066564, 26076669, 27573854, 15144854, 15774457, 26799529, 27393118, 27098685, 9197268, 29398121, 9484385, 23210740, 22188655, 24392030, 23505409, 24066883, 25393002, 23669636, 24795107, 23607785, 23941114, 28012952, 25330418, 25297088, 26405178, 15981014, 28416701, 30528390, 27028329, 33981801, 32954426, 17489854, 9389595, 10025809, 20628651, 37750340, 37229975, 37198191, 28900007) -

Autosomal dominant Parkinson disease 4 Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although both toxic gain-of-function and loss-of-function have been suggested (PMID: 26858591). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the annotated synuclein domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Ala53Val) has been reported twice as a variant of unknown significance in ClinVar. It has also been reported in an individual diagnosed with Parkinson disease (PMID:28666710). Another variant, p.(Ala53Glu), has been reported in three individuals affected with Parkinson disease from one family (PMID:30423204). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many unrelated families in individuals with clinical diagnoses of Parkinson disease (PMID:9197268, 10482268, 29233723, 28012952, 27393118). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient derived iSPCs recreated the neuronal phenotype seen in Parkinson disease (PMID:28416701). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal dominant Parkinson disease 1 Pathogenic:1

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 Pathogenic:1

Feb 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.38	.;T;.;T;T;T;T;.;T
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;.;.
PhyloP100		3.5
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
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;