22-39374345-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004711.5(SYNGR1):c.129C>G(p.Ile43Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNGR1 NM_004711.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.690

Genes affected

SYNGR1 (HGNC:11498): (synaptogyrin 1) This gene encodes an integral membrane protein associated with presynaptic vesicles in neuronal cells. The exact function of this protein is unclear, but studies of a similar murine protein suggest that it functions in synaptic plasticity without being required for synaptic transmission. The gene product belongs to the synaptogyrin gene family. Three alternatively spliced variants encoding three different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGR1	NM_004711.5	c.129C>G	p.Ile43Met	missense_variant	2/4	ENST00000328933.10
SYNGR1	NM_145738.3	c.132C>G	p.Ile44Met	missense_variant	2/4
SYNGR1	NM_145731.4	c.129C>G	p.Ile43Met	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGR1	ENST00000328933.10	c.129C>G	p.Ile43Met	missense_variant	2/4	1	NM_004711.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727168

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.129C>G (p.I43M) alteration is located in exon 2 (coding exon 2) of the SYNGR1 gene. This alteration results from a C to G substitution at nucleotide position 129, causing the isoleucine (I) at amino acid position 43 to be replaced by a methionine (M). 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	0.52
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.71
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.8	M;.;.;M;.
MutationTaster	Benign	0.98	D;D;D;D;D
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.93
MutPred		0.89		Loss of catalytic residue at I43 (P = 0.0331);Loss of catalytic residue at I43 (P = 0.0331);Loss of catalytic residue at I43 (P = 0.0331);Loss of catalytic residue at I43 (P = 0.0331);.;
MVP		0.19
MPC		1.0
ClinPred		0.98	D
GERP RS		-9.3
Varity_R		0.84
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39770350;