chr4-89815772-G-A

Variant names:

• chr4-89815772-G-A
• rs1442145
• NM_000345.4:c.306+6474C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000345.4(SNCA):​c.306+6474C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 151,982 control chromosomes in the GnomAD database, including 35,070 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (35070 hom., cov: 33)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 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.306+6474C>T		intron	N/A	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.306+6474C>T		intron	N/A	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.306+6474C>T		intron	N/A	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.306+6474C>T		intron	N/A	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.306+6474C>T		intron	N/A	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.264+6474C>T		intron	N/A	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102468 AN: 151866 Hom.: 35047 Cov.: 33

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.661

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.675 AC: 102535 AN: 151982 Hom.: 35070 Cov.: 33 AF XY: 0.670 AC XY: 49765 AN XY: 74282

African (AFR) AF: 0.622 AC: 25804 AN: 41454

American (AMR) AF: 0.597 AC: 9115 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2088 AN: 3472

East Asian (EAS) AF: 0.661 AC: 3410 AN: 5162

South Asian (SAS) AF: 0.502 AC: 2420 AN: 4816

European-Finnish (FIN) AF: 0.742 AC: 7829 AN: 10554

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49577 AN: 67940

Other (OTH) AF: 0.658 AC: 1389 AN: 2112

Alfa AF: 0.689 Hom.: 4756

Bravo AF: 0.668

Asia WGS AF: 0.571 AC: 1979 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		0.050
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: rs1442145; hg19: chr4-90736923;