rs3734353

Variant names:

• chr6-100448693-T-G
• rs3734353
• NM_005068.3:c.544-15A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005068.3(SIM1):​c.544-15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,602,516 control chromosomes in the GnomAD database, including 75,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7178 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68220 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.284
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• obesity due to SIM1 deficiency

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-100448693-T-G is Benign according to our data. Variant chr6-100448693-T-G is described in ClinVar as Benign. ClinVar VariationId is 354686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3	c.544-15A>C		intron_variant	Intron 6 of 11	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.544-15A>C		intron_variant	Intron 6 of 11		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.544-15A>C		intron_variant	Intron 6 of 11	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4	c.544-15A>C		intron_variant	Intron 5 of 10	1		ENSP00000262901.4

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46019 AN: 151762 Hom.: 7170 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.315 AC: 76365 AN: 242440 AF XY: 0.307

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.304 AC: 440343 AN: 1450636 Hom.: 68220 Cov.: 32 AF XY: 0.301 AC XY: 217102 AN XY: 721494

African (AFR) AF: 0.267 AC: 8913 AN: 33424

American (AMR) AF: 0.429 AC: 19118 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6415 AN: 26048

East Asian (EAS) AF: 0.451 AC: 17878 AN: 39602

South Asian (SAS) AF: 0.232 AC: 19957 AN: 86068

European-Finnish (FIN) AF: 0.328 AC: 15063 AN: 45992

Middle Eastern (MID) AF: 0.322 AC: 1806 AN: 5610

European-Non Finnish (NFE) AF: 0.300 AC: 333130 AN: 1109206

Other (OTH) AF: 0.300 AC: 18063 AN: 60172

GnomAD4 genome AF: 0.303 AC: 46054 AN: 151880 Hom.: 7178 Cov.: 32 AF XY: 0.308 AC XY: 22846 AN XY: 74214

African (AFR) AF: 0.270 AC: 11189 AN: 41436

American (AMR) AF: 0.375 AC: 5726 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2284 AN: 5142

South Asian (SAS) AF: 0.228 AC: 1094 AN: 4794

European-Finnish (FIN) AF: 0.342 AC: 3608 AN: 10544

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20349 AN: 67896

Other (OTH) AF: 0.280 AC: 589 AN: 2106

Alfa AF: 0.295 Hom.: 9968

Bravo AF: 0.308

Asia WGS AF: 0.306 AC: 1062 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity due to SIM1 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.37
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3734353; hg19: chr6-100896569; COSMIC: COSV53490132;