rs41318039

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.522

Publications

5 publications found

Variant links:

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

SIM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3 link	c.*113A>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000369208.8	NP_005059.2	P81133
SIM1	NM_001374769.1 link	c.*113A>T		3_prime_UTR_variant	Exon 12 of 12		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8 link	c.*113A>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_005068.3	ENSP00000358210.4		P81133
SIM1	ENST00000262901.4 link	c.*113A>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000262901.4		P81133

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4516

AN:

152208

Hom.:

103

Cov.:

show subpopulations

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.:

AF XY:

0.0399

AC XY:

20498

AN XY:

514322

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1886

3772

5659

7545

9431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1148

2296

3444

4592

5740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0296

AC:

4514

AN:

152326

Hom.:

103

Cov.:

AF XY:

0.0288

AC XY:

2143

AN XY:

74492

show subpopulations

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:

AN:

5184

South Asian (SAS)

AF:

0.0180

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0372

AC:

395

AN:

10626

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0429

AC:

2916

AN:

68020

Other (OTH)

AF:

0.0383

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

232

464

695

927

1159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.0291

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

-0.48

CADD

Benign

6.8

(source)

DANN

Benign

0.81

PhyloP100

0.52

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over