Genetic Variant NM_000345.4:c.-26+608A>G (chr4-89836354-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000345.4(SNCA):c.-26+608A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 152,666 control chromosomes in the GnomAD database, including 46,055 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 0.78 ( 45882 hom., cov: 32)

Exomes 𝑓: 0.80 ( 173 hom. )

Consequence

SNCA
NM_000345.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.336

Publications

24 publications found

Variant links:

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 links:

SNCA-AS1 (HGNC:50600): (SNCA antisense RNA 1)

SNCA-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4 link	c.-26+608A>G		intron_variant	Intron 1 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8 link	c.-26+608A>G		intron_variant	Intron 1 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes

AF:

0.775

AC:

117874

AN:

152032

Hom.:

45852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.818

Gnomad AMR

AF:

0.733

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.862

Gnomad SAS

AF:

0.665

Gnomad FIN

AF:

0.816

Gnomad MID

AF:

0.710

Gnomad NFE

AF:

0.781

Gnomad OTH

AF:

0.766

GnomAD4 exome

AF:

0.798

AC:

412

AN:

516

Hom.:

173

Cov.:

AF XY:

0.818

AC XY:

270

AN XY:

330

show subpopulations

African (AFR)

AF:

0.333

AC:

AN:

American (AMR)

AF:

0.833

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.929

AC:

AN:

South Asian (SAS)

AF:

0.688

AC:

AN:

European-Finnish (FIN)

AF:

0.875

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.799

AC:

318

AN:

398

Other (OTH)

AF:

0.850

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.775

AC:

117949

AN:

152150

Hom.:

45882

Cov.:

AF XY:

0.772

AC XY:

57482

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.779

AC:

32347

AN:

41500

American (AMR)

AF:

0.732

AC:

11190

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2451

AN:

3472

East Asian (EAS)

AF:

0.862

AC:

4449

AN:

5162

South Asian (SAS)

AF:

0.665

AC:

3202

AN:

4816

European-Finnish (FIN)

AF:

0.816

AC:

8653

AN:

10606

Middle Eastern (MID)

AF:

0.716

AC:

209

AN:

292

European-Non Finnish (NFE)

AF:

0.781

AC:

53090

AN:

67996

Other (OTH)

AF:

0.763

AC:

1612

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1378

2755

4133

5510

6888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.775

Hom.:

5696

Bravo

AF:

0.775

Asia WGS

AF:

0.751

AC:

2613

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-0.34

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over