Genetic Variant NM_004209.6:c.125C>T (chr16-1991999-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004209.6(SYNGR3):c.125C>T(p.Pro42Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SYNGR3
NM_004209.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Variant links:

Genes affected

SYNGR3 (HGNC:11501): (synaptogyrin 3) This gene encodes an integral membrane protein. The exact function of this protein is unclear, but studies of a similar murine protein suggest that it is a synaptic vesicle protein that also interacts with the dopamine transporter. The gene product belongs to the synaptogyrin gene family. [provided by RefSeq, Dec 2010]

SYNGR3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2895877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGR3	NM_004209.6 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 2 of 4	ENST00000248121.7	NP_004200.2	O43761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNGR3	ENST00000248121.7 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 2 of 4	1	NM_004209.6	ENSP00000248121.2	O43761
SYNGR3	ENST00000568896.1 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 3 of 4	5		ENSP00000454756.1	H3BNA6
SYNGR3	ENST00000563869.1 link	c.57C>T	p.Ala19Ala	synonymous_variant	Exon 2 of 4	2		ENSP00000455344.1	H3BPJ5
SYNGR3	ENST00000562045 link	c.-141C>T		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000455577.1	H3BQ28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>T (p.P42L) alteration is located in exon 2 (coding exon 2) of the SYNGR3 gene. This alteration results from a C to T substitution at nucleotide position 125, causing the proline (P) at amino acid position 42 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;.;T

Eigen

Benign

-0.076

Eigen_PC

Benign

0.086

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

N;.;N

REVEL

Benign

0.063

Sift

Uncertain

0.026

D;.;T

Sift4G

Uncertain

0.036

D;D;T

Polyphen

0.10

B;.;.

Vest4

0.51

MutPred

0.61

Gain of catalytic residue at P42 (P = 0.0123);Gain of catalytic residue at P42 (P = 0.0123);.;

MVP

0.29

MPC

0.69

ClinPred

0.88

GERP RS

4.5

Varity_R

0.33

gMVP

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over