Genetic Variant NM_003087.3:c.220G>T (chr10-86960057-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003087.3(SNCG):c.220G>T(p.Val74Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V74I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SNCG
NM_003087.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.71

Publications

0 publications found

Variant links:

Genes affected

SNCG (HGNC:11141): (synuclein gamma) This gene encodes a member of the synuclein family of proteins which are believed to be involved in the pathogenesis of neurodegenerative diseases. Mutations in this gene have also been associated with breast tumor development. [provided by RefSeq, Jan 2010]

SNCG links:

MMRN2 (HGNC:19888): (multimerin 2) This gene encodes a protein belonging to the member of elastin microfibril interface-located (EMILIN) protein family. This family member is an extracellular matrix glycoprotein that can interfere with tumor angiogenesis and growth. It serves as a transforming growth factor beta antagonist and can interfere with the VEGF-A/VEGFR2 pathway. A related pseudogene has been identified on chromosome 6. [provided by RefSeq, Aug 2012]

MMRN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29558414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003087.3. 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
	SNCG	NM_003087.3	MANE Select	c.220G>T	p.Val74Phe	missense	Exon 3 of 5	NP_003078.2	O76070
	SNCG	NM_001330120.2		c.272G>T	p.Arg91Leu	missense	Exon 5 of 7	NP_001317049.1	F8W754

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNCG	ENST00000372017.4	TSL:1 MANE Select	c.220G>T	p.Val74Phe	missense	Exon 3 of 5	ENSP00000361087.3	O76070
SNCG	ENST00000930521.1		c.220G>T	p.Val74Phe	missense	Exon 4 of 6	ENSP00000600580.1
SNCG	ENST00000951192.1		c.220G>T	p.Val74Phe	missense	Exon 5 of 7	ENSP00000621251.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460700

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

85952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111736

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0057

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.32

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.30

MetaSVM

Uncertain

0.44

PhyloP100

5.7

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Benign

0.10

Vest4

0.33

MutPred

0.46

Gain of stability (P = 0.0614)

MVP

0.69

ClinPred

0.99

GERP RS

3.8

Varity_R

0.60

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over