NM_005068.3:c.1054C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 6.19

Variant links:

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]

SIM1 links:

SIM1-AS1 (HGNC:40530): (SIM1 antisense RNA 1)

SIM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23204595).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152004) while in subpopulation NFE AF= 0.000309 (21/67984). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3 link	c.1054C>T	p.Pro352Ser	missense_variant	Exon 10 of 12	ENST00000369208.8	NP_005059.2	P81133
SIM1	NM_001374769.1 link	c.1054C>T	p.Pro352Ser	missense_variant	Exon 10 of 12		NP_001361698.1
SIM1-AS1	NR_187148.1 link	n.891-6215G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8 link	c.1054C>T	p.Pro352Ser	missense_variant	Exon 10 of 12	1	NM_005068.3	ENSP00000358210.4		P81133
SIM1	ENST00000262901.4 link	c.1054C>T	p.Pro352Ser	missense_variant	Exon 9 of 11	1		ENSP00000262901.4		P81133

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

250782

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000292

AC:

427

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

209

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000364

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000151

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000309

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000536

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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.062

T;T

Eigen

Benign

-0.040

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.28

N;N

REVEL

Benign

0.13

Sift

Benign

0.55

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0040

B;B

Vest4

0.51

MutPred

0.21

Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);

MVP

0.043

MPC

0.030

ClinPred

0.12

GERP RS

5.8

Varity_R

0.076

gMVP

0.31

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