rs375440874

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006950.3(SYN1):c.1325T>C(p.Leu442Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,186,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L442L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 16 hem., cov: 23)

Exomes 𝑓: 0.000053 ( 0 hom. 12 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.976

Variant links:

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]

SYN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01687032).

BP6

Variant X-47574756-A-G is Benign according to our data. Variant chrX-47574756-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193940.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3 linkuse as main transcript	c.1325T>C	p.Leu442Pro	missense_variant	11/13	ENST00000295987.13
SYN1	NM_133499.2 linkuse as main transcript	c.1325T>C	p.Leu442Pro	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13 linkuse as main transcript	c.1325T>C	p.Leu442Pro	missense_variant	11/13	2	NM_006950.3	P3	P17600-1
SYN1	ENST00000340666.5 linkuse as main transcript	c.1325T>C	p.Leu442Pro	missense_variant	11/13	1		A1	P17600-2
SYN1	ENST00000640721.1 linkuse as main transcript	c.2T>C	p.Leu1Pro	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

111639

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

33873

show subpopulations

Gnomad AFR

AF:

0.00189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.000128

AC:

AN:

132407

Hom.:

AF XY:

0.000139

AC XY:

AN XY:

43099

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000530

AC:

AN:

1074462

Hom.:

Cov.:

AF XY:

0.0000343

AC XY:

AN XY:

350126

show subpopulations

Gnomad4 AFR exome

AF:

0.00183

Gnomad4 AMR exome

AF:

0.0000329

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:

0.00

Gnomad4 OTH exome

AF:

0.000177

GnomAD4 genome

AF:

0.000528

AC:

AN:

111687

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

AN XY:

33931

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.000548

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000885

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2013	p.Leu442Pro (CTG>CCG): c.1325 T>C in exon 11 of the SYN1 gene (NM_133499.2) The Leu442Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Although both Leucine and Proline are uncharged, non-polar amino acid residues, the gain of a Proline may affect the secondary structure of the synapsin-1 protein. Leu442Pro alters a position that is not well conserved in the protein and to our knowledge, other missense mutations have not been reported in this region of the protein. Several in-silico algorithms predict Leu442Pro may be benign, while another model suggests it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, it is unclear whether Leu442Pro is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2015	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.16

T;.;.

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.39

T;T;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.65

N;N;.

REVEL

Benign

0.021

Sift

Benign

0.15

T;T;.

Sift4G

Benign

0.34

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.16

MVP

0.21

MPC

1.1

ClinPred

0.034

GERP RS

1.4

Varity_R

0.16

gMVP

0.35

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