rs41315244

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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
• inherited obesity

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005068.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	NM_005068.3	MANE Select	c.-127T>C		5_prime_UTR	Exon 2 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.-127T>C		5_prime_UTR	Exon 2 of 12	NP_001361698.1	P81133

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.-127T>C		5_prime_UTR	Exon 2 of 12	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.-127T>C		5_prime_UTR	Exon 1 of 11	ENSP00000262901.4	P81133
	SIM1	ENST00000511871.1	TSL:1	n.617T>C		non_coding_transcript_exon	Exon 2 of 2

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

African (AFR) AF: 0.00760 AC: 137 AN: 18024

American (AMR) AF: 0.0269 AC: 777 AN: 28882

Ashkenazi Jewish (ASJ) AF: 0.0659 AC: 1049 AN: 15912

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35710

South Asian (SAS) AF: 0.0153 AC: 825 AN: 53750

European-Finnish (FIN) AF: 0.0385 AC: 1494 AN: 38774

Middle Eastern (MID) AF: 0.00812 AC: 33 AN: 4066

European-Non Finnish (NFE) AF: 0.0553 AC: 26794 AN: 484470

Other (OTH) AF: 0.0439 AC: 1537 AN: 35008

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

African (AFR) AF: 0.00921 AC: 383 AN: 41568

American (AMR) AF: 0.0329 AC: 503 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.0421 AC: 447 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0553 AC: 3763 AN: 68026

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0455 Hom.: 75

Bravo AF: 0.0343

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Obesity due to SIM1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.3
DANN	Benign	0.55
PhyloP100		0.96
PromoterAI		-0.016	Neutral
Mutation Taster		=298/2	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: rs41315244; hg19: chr6-100911471; COSMIC: COSV53490980;