SIM1

protein-coding

SIM bHLH transcription factor 1, the group of PAS domain containing|Basic helix-loop-helix proteins

Gene summary

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]

MANE transcript

NM_005068.3

Inheritance

AD, AR

ClinVar variants

P:19U:358B:140

Top phenotype

obesity due to SIM1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr6:100,385,009-100,464,921

External References & Databases

Ensembl (ENSG00000112246)

Transcript & Mutation Effects

hg38 • Region Span ~79.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inherited obesitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019182

Submitter: PanelApp Australia

obesity due to SIM1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018244

Submitter: Orphanet

obesity due to SIM1 deficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018244

Submitter: G2P

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIM1 variants in ClinVar

15 Conditions Cataloged

SIM1-related disorderTotal: 358

not providedTotal: 176

Inborn genetic diseasesTotal: 95

Obesity due to SIM1 deficiencyTotal: 40

not specifiedTotal: 26

Monogenic diabetesTotal: 7

Early onset severe obesityTotal: 4

SIM1-associated metabolic syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005068.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	121 clinvar	3 clinvar	134
missense		1 clinvar	336 clinvar	15 clinvar	1 clinvar	353
nonsense		6 clinvar	5 clinvar			11
start loss						0
frameshift	3 clinvar	6 clinvar	6 clinvar			15
splice donor/acceptor (+/-2bp)		3 clinvar	1 clinvar			4
Total	3	16	358	136	4	517

Highest pathogenic variant AF is 0.0000068150616

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005068.3	RefSeq	NP_005059.2	11	MANE Select
ENST00000369208.8	Ensembl	ENSP00000358210.4	11	MANE Select
NM_001374769.1	RefSeq	NP_001361698.1	11	Standard
ENST00000262901.4	Ensembl	ENSP00000262901.4	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sim1a	Danio rerio	Structure: dopaminergic neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

sim1a

Danio rerio

Structure: dopaminergic neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ureteric bud development
regulation of transcription by RNA polymerase II
nervous system development
cell differentiation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein heterodimerization activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369208
Coding exons: 11
Length: 79915
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.715	405	448	0.905	0.0000235	5015
Missense (PolyPhen)		129	174.87	0.73771		1996
Synonymous	-0.308	194	189	1.03	0.0000110	1511
Loss of Function	4.96	4	36.2	0.111	0.00000192	407

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.;

Recessive Scores

pRec: 0.171

Intolerance Scores

LoFtool: 0.300
RVIS EVS: -0.82
RVIS percentile EVS: 11.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.686

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium