rs1395119

chr6-100390013-T-Achr6-100390013-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005068.3(SIM1):c.*348A>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 0.378 in 385,692 control chromosomes in the GnomAD database, including 30,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10131 hom., cov: 32)
  • Exomes 𝑓: 0.40 (20159 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.277

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=-0.93).
• BP6: Variant 6-100390013-T-A is Benign according to our data. Variant chr6-100390013-T-A is described in ClinVar as [Benign]. Clinvar id is 354670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM1	NM_005068.3	c.*348A>T		3_prime_UTR_variant	12/12	ENST00000369208.8
SIM1	NM_001374769.1	c.*348A>T		3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM1	ENST00000369208.8	c.*348A>T		3_prime_UTR_variant	12/12	1	NM_005068.3	P1
SIM1	ENST00000262901.4	c.*348A>T		3_prime_UTR_variant	11/11	1		P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53386 AN: 152000 Hom.: 10109 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.395 AC: 92325 AN: 233576 Hom.: 20159 Cov.: 0 AF XY: 0.394 AC XY: 46915 AN XY: 119118

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.755

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.351 AC: 53444 AN: 152116 Hom.: 10131 Cov.: 32 AF XY: 0.357 AC XY: 26514 AN XY: 74366

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.343

Alfa AF: 0.360 Hom.: 1290

Bravo AF: 0.352

Asia WGS AF: 0.507 AC: 1758 AN: 3474

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 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	-0.93
Cadd	Benign	0.047
Dann	Benign	0.51

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: rs1395119; hg19: chr6-100837889;