16-1991999-C-T

Variant names:

• chr16-1991999-C-T
• rs1486707673
• NM_004209.6:c.125C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

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	c.125C>T	p.Pro42Leu	missense_variant	Exon 2 of 4	ENST00000248121.7	NP_004200.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442518 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716136

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Pathogenic	0.92	D
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	D
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

Other links and lift over

dbSNP: rs1486707673; hg19: chr16-2042000;