rs41315244

Variant names:

• chr6-100463595-A-G
• rs41315244
• NM_005068.3:c.-127T>C

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.-127T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 866,910 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (136 hom., cov: 32)
  • Exomes 𝑓: 0.046 (876 hom.)
• Consequence: SIM1 NM_005068.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.957

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=-0.79).
• BP6: Variant 6-100463595-A-G is Benign according to our data. Variant chr6-100463595-A-G is described in ClinVar as [Benign]. Clinvar id is 354688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3	c.-127T>C		5_prime_UTR_variant	Exon 2 of 12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.-127T>C		5_prime_UTR_variant	Exon 2 of 12		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.-127T>C		5_prime_UTR_variant	Exon 2 of 12	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4	c.-127T>C		5_prime_UTR_variant	Exon 1 of 11	1		ENSP00000262901.4
SIM1	ENST00000511871.1	n.617T>C		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5473 AN: 152196 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0553

Gnomad OTH AF: 0.0339

GnomAD4 exome AF: 0.0457 AC: 32648 AN: 714596 Hom.: 876 Cov.: 9 AF XY: 0.0449 AC XY: 16587 AN XY: 369476

Gnomad4 AFR exome AF: 0.00760

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0659

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0385

Gnomad4 NFE exome AF: 0.0553

Gnomad4 OTH exome AF: 0.0439

GnomAD4 genome AF: 0.0359 AC: 5470 AN: 152314 Hom.: 136 Cov.: 32 AF XY: 0.0346 AC XY: 2577 AN XY: 74480

Gnomad4 AFR AF: 0.00921

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.0553

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0488 Hom.: 40

Bravo AF: 0.0343

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity due to SIM1 deficiency Benign:1

Jan 12, 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	-0.79
CADD	Benign	8.3
DANN	Benign	0.55

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: rs41315244; hg19: chr6-100911471; COSMIC: COSV53490980;