rs41318039

Variant names:

• chr6-100390248-T-A
• rs41318039
• NM_005068.3:c.*113A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 103 AD,AR gene

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.*113A>T		3_prime_UTR	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.*113A>T		3_prime_UTR	Exon 12 of 12	NP_001361698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.*113A>T		3_prime_UTR	Exon 12 of 12	ENSP00000358210.4
	SIM1	ENST00000262901.4	TSL:1	c.*113A>T		3_prime_UTR	Exon 11 of 11	ENSP00000262901.4
	SIM1	ENST00000900753.1		c.*113A>T		3_prime_UTR	Exon 12 of 12	ENSP00000570812.1

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

African (AFR) AF: 0.00747 AC: 175 AN: 23418

American (AMR) AF: 0.0229 AC: 641 AN: 27996

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 1077 AN: 17856

East Asian (EAS) AF: 0.000161 AC: 6 AN: 37244

South Asian (SAS) AF: 0.0204 AC: 1251 AN: 61372

European-Finnish (FIN) AF: 0.0347 AC: 1318 AN: 38018

Middle Eastern (MID) AF: 0.0436 AC: 173 AN: 3968

European-Non Finnish (NFE) AF: 0.0449 AC: 34474 AN: 767138

Other (OTH) AF: 0.0408 AC: 1836 AN: 45020

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

African (AFR) AF: 0.00815 AC: 339 AN: 41578

American (AMR) AF: 0.0252 AC: 385 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4824

European-Finnish (FIN) AF: 0.0372 AC: 395 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0429 AC: 2916 AN: 68020

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0145 Hom.: 7

Bravo AF: 0.0291

ClinVar

ClinVar submissions as Germline

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	-0.48
CADD	Benign	6.8
DANN	Benign	0.81
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism

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: rs41318039; hg19: chr6-100838124;