rs3734353

Positions:

• chr6-100448693-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SIM1	NM_005068.3	c.544-15A>C		intron_variant		ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.544-15A>C		intron_variant			NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.544-15A>C		intron_variant		1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4	c.544-15A>C		intron_variant		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

GnomAD3 exomes AF: 0.315 AC: 76365 AN: 242440 Hom.: 12657 AF XY: 0.307 AC XY: 40369 AN XY: 131568

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 SAS exome AF: 0.230

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

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.300

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

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.280

Alfa AF: 0.294 Hom.: 1991

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Obesity due to SIM1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Other links and lift over

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