chr4-89720189-T-C

Variant names:

• chr4-89720189-T-C
• rs356220
• ENST00000673902.1:c.390+9005A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000673902.1(SNCA):c.390+9005A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000673902.1 is not a MANE Select or MANE Plus Clinical transcript for SNCA; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.542 (AC=81,531) in the gnomAD database across 150,538 control chromosomes, including 23,127 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.633. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (23127 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: SNCA ENST00000673902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.66
• Publications: 115 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: 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

ENSG00000251095 (HGNC:53614): ()

LOC124900602 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6327 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000673902.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SNCA ENST00000673902.1		c.390+9005A>G	intron	Intron 5 of 6	Prot: ENSP00000501102.1 UniProt:
	ENSG00000251095 ENST00000508021.5	TSL:4	n.448-6195T>C	intron	Intron 4 of 4	Prot:
	ENSG00000251095 ENST00000659878.1		n.480-6195T>C	intron	Intron 2 of 2	Prot:

SNCA ENST00000673902.1

HGVSc / HGVSpc.390+9005A>G

Exon rankIntron 5 of 6

intron

Prot: ENSP00000501102.1UniProt: A0A669KB41

ENSG00000251095 ENST00000508021.5

TSL:4

HGVSc / HGVSpn.448-6195T>C

Exon rankIntron 4 of 4

intron

Prot:

ENSG00000251095 ENST00000659878.1

HGVSc / HGVSpn.480-6195T>C

Exon rankIntron 2 of 2

intron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.542	AC:81496	Hom:23120	AN:150426	Cov:30
GnomAD4 exome Warning	AF:	AC:0	Hom:0	AN:0	Cov:0
GnomAD4 genome	AF: 0.542	AC:81531	Hom:23127	AN:150538	Cov:30
TOPMed (Bravo)	AF: 0.517	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.600	AC:431923	Hom:132389	AN:720348	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.568	AC:1331	Hom:373	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.465	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.613	AC:184	Hom:	AN:300	Cov:
Korea4K (4,157 Koreans)	AF: 0.459	AC:3305	Hom:	AN:7208	Cov:
Qatari Genome	AF: 0.506	AC:89	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.411	AC:50179	Hom:10328	AN:122022	Cov:
Turkish Variome	AF: 0.633	AC:972	Hom:305	AN:1536	Cov:

Showing 12 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.2
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.50
DANN	Benign	0.76
GPN-Star LLR	N/A	2.5
GPN-Star score	N/A	-2.1
PhyloP100	Benign	-1.7

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs356220;

hg19: chr4-90641340;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar