NM_006950.3:c.1310C>T

Variant names:

• chrX-47574771-G-A
• rs895517774
• NM_006950.3:c.1310C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006950.3(SYN1):​c.1310C>T​(p.Pro437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000592 in 1,182,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000056 (0 hom. 1 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.524

Genes affected

SYN1 (HGNC:11494): (synapsin I) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.092044294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1310C>T	p.Pro437Leu	missense_variant	Exon 11 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1310C>T	p.Pro437Leu	missense_variant	Exon 11 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1310C>T	p.Pro437Leu	missense_variant	Exon 11 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1310C>T	p.Pro437Leu	missense_variant	Exon 11 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.-14C>T		upstream_gene_variant		5		ENSP00000492857.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111244 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33506

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000560 AC: 6 AN: 1070986 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 1 AN XY: 347630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000332

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: 0.00000242

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111244 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33506

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000934

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:1

Mar 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with SYN1-related conditions. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 437 of the SYN1 protein (p.Pro437Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 465088). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Uncertain	0.59	D;.
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.040
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.033	D;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.38		Loss of glycosylation at P437 (P = 0.0485);Loss of glycosylation at P437 (P = 0.0485);
MVP		0.14
MPC		0.79
ClinPred		0.10	T
GERP RS		2.4
Varity_R		0.089
gMVP		0.29

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: rs895517774; hg19: chrX-47434170;