NM_000345.4:c.*501C>T

Variant names:

• chr4-89726127-G-A
• rs17016074
• NM_000345.4:c.*501C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000345.4(SNCA):​c.*501C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 152,826 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (422 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (0 hom.)
• Consequence: SNCA NM_000345.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.25
• Publications: 18 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

LOC124900602 (HGNC:):

ENSG00000251095 (HGNC:53614):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-89726127-G-A is Benign according to our data. Variant chr4-89726127-G-A is described in ClinVar as Benign. ClinVar VariationId is 350098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

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.*501C>T		3_prime_UTR	Exon 6 of 6	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.*501C>T		3_prime_UTR	Exon 6 of 6	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.*501C>T		3_prime_UTR	Exon 6 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.*501C>T		3_prime_UTR	Exon 6 of 6	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.*501C>T		3_prime_UTR	Exon 6 of 6	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.*501C>T		3_prime_UTR	Exon 5 of 5	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6788 AN: 151852 Hom.: 420 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.000758

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0460

GnomAD4 exome AF: 0.00351 AC: 3 AN: 854 Hom.: 0 Cov.: 0 AF XY: 0.00591 AC XY: 3 AN XY: 508

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 62

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 22

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00641 AC: 2 AN: 312

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.0448 AC: 6805 AN: 151972 Hom.: 422 Cov.: 32 AF XY: 0.0436 AC XY: 3236 AN XY: 74256

African (AFR) AF: 0.138 AC: 5706 AN: 41412

American (AMR) AF: 0.0233 AC: 355 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4814

European-Finnish (FIN) AF: 0.000758 AC: 8 AN: 10552

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.00662 AC: 450 AN: 67980

Other (OTH) AF: 0.0455 AC: 96 AN: 2110

Alfa AF: 0.0326 Hom.: 41

Bravo AF: 0.0509

Asia WGS AF: 0.0170 AC: 59 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17016074; hg19: chr4-90647278;