rs3734354
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005068.3(SIM1):c.1054C>T(p.Pro352Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000279 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352T) has been classified as Benign.
Frequency
Consequence
NM_005068.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIM1 | NM_005068.3 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 | ENST00000369208.8 | |
SIM1-AS1 | XR_942815.4 | n.891-6215G>A | intron_variant, non_coding_transcript_variant | ||||
SIM1 | NM_001374769.1 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIM1 | ENST00000369208.8 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 | 1 | NM_005068.3 | P1 | |
SIM1 | ENST00000262901.4 | c.1054C>T | p.Pro352Ser | missense_variant | 9/11 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152004Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 250782Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135536
GnomAD4 exome AF: 0.000292 AC: 427AN: 1461668Hom.: 0 Cov.: 33 AF XY: 0.000287 AC XY: 209AN XY: 727114
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74212
ClinVar
Submissions by phenotype
Obesity due to SIM1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
SIM1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 13, 2023 | The SIM1 c.1054C>T variant is predicted to result in the amino acid substitution p.Pro352Ser. This variant has been reported in an individual with Prader-Willi-like syndrome (Geets et al. 2016. PubMed ID: 26795956). However, this variant was shown to have functional activity similar (92%) to wild type SIM1 activity (https://www.rhythmtx.com/wp-content/uploads/2021/11/Vogel-Biochemical-Characterization-of-SIM1.pdf; Vogel et al. 2022. https://doi.org/10.1016/j.gim.2022.01.050). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at