rs41318039

Positions:

• chr6-100390248-T-A
• chr6-100390248-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005068.3(SIM1):​c.*113A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,174,356 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (103 hom., cov: 32)
  • Exomes 𝑓: 0.040 (948 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.522

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-100390248-T-A is Benign according to our data. Variant chr6-100390248-T-A is described in ClinVar as [Benign]. Clinvar id is 354672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0296 (4514/152326) while in subpopulation NFE AF= 0.0429 (2916/68020). AF 95% confidence interval is 0.0416. There are 103 homozygotes in gnomad4. There are 2143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4514 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM1	NM_005068.3	c.*113A>T		3_prime_UTR_variant	12/12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.*113A>T		3_prime_UTR_variant	12/12		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.*113A>T		3_prime_UTR_variant	12/12	1	NM_005068.3	ENSP00000358210	P1
SIM1	ENST00000262901.4	c.*113A>T		3_prime_UTR_variant	11/11	1		ENSP00000262901	P1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4516 AN: 152208 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00815

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0429

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0401 AC: 40951 AN: 1022030 Hom.: 948 Cov.: 13 AF XY: 0.0399 AC XY: 20498 AN XY: 514322

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0603

Gnomad4 EAS exome AF: 0.000161

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0347

Gnomad4 NFE exome AF: 0.0449

Gnomad4 OTH exome AF: 0.0408

GnomAD4 genome AF: 0.0296 AC: 4514 AN: 152326 Hom.: 103 Cov.: 32 AF XY: 0.0288 AC XY: 2143 AN XY: 74492

Gnomad4 AFR AF: 0.00815

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0573

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.0429

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0145 Hom.: 7

Bravo AF: 0.0291

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity due to SIM1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.48
CADD	Benign	6.8
DANN	Benign	0.81

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: rs41318039; hg19: chr6-100838124;