rs375440874
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_006950.3(SYN1):āc.1325T>Cā(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
Consequence
NM_006950.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYN1 | NM_006950.3 | c.1325T>C | p.Leu442Pro | missense_variant | 11/13 | ENST00000295987.13 | |
SYN1 | NM_133499.2 | c.1325T>C | p.Leu442Pro | missense_variant | 11/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYN1 | ENST00000295987.13 | c.1325T>C | p.Leu442Pro | missense_variant | 11/13 | 2 | NM_006950.3 | P3 | |
SYN1 | ENST00000340666.5 | c.1325T>C | p.Leu442Pro | missense_variant | 11/13 | 1 | A1 | ||
SYN1 | ENST00000640721.1 | c.2T>C | p.Leu1Pro | missense_variant | 1/2 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000520 AC: 58AN: 111639Hom.: 0 Cov.: 23 AF XY: 0.000443 AC XY: 15AN XY: 33873
GnomAD3 exomes AF: 0.000128 AC: 17AN: 132407Hom.: 0 AF XY: 0.000139 AC XY: 6AN XY: 43099
GnomAD4 exome AF: 0.0000530 AC: 57AN: 1074462Hom.: 0 Cov.: 31 AF XY: 0.0000343 AC XY: 12AN XY: 350126
GnomAD4 genome ? AF: 0.000528 AC: 59AN: 111687Hom.: 0 Cov.: 23 AF XY: 0.000472 AC XY: 16AN XY: 33931
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 16, 2015 | - - |
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). - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at