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 (★).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
SIM1
NM_005068.3 missense
NM_005068.3 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 6.19
Genes affected
SIM1 (HGNC:10882): (SIM bHLH transcription factor 1) SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. SIM1 transcript was detected only in fetal kidney out of various adult and fetal tissues tested. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis,it was proposed that the human SIM gene is a candidate for involvement in certain dysmorphic features (particularly the facial and skull characteristics), abnormalities of brain development, and/or cognitive disability of Down syndrome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.23204595).
BS2
High AC in GnomAd4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIM1 | NM_005068.3 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 | ENST00000369208.8 | NP_005059.2 | |
SIM1 | NM_001374769.1 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 | NP_001361698.1 | ||
SIM1-AS1 | NR_187148.1 | n.891-6215G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIM1 | ENST00000369208.8 | c.1054C>T | p.Pro352Ser | missense_variant | 10/12 | 1 | NM_005068.3 | ENSP00000358210.4 | ||
SIM1 | ENST00000262901.4 | c.1054C>T | p.Pro352Ser | missense_variant | 9/11 | 1 | ENSP00000262901.4 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152004Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 250782Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135536
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GnomAD4 exome AF: 0.000292 AC: 427AN: 1461668Hom.: 0 Cov.: 33 AF XY: 0.000287 AC XY: 209AN XY: 727114
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74212
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
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, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2024 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at