rs3734355

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005068.3(SIM1):c.1112C>T(p.Ala371Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,556 control chromosomes in the GnomAD database, including 21,646 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1742 hom., cov: 32)

Exomes 𝑓: 0.15 ( 19904 hom. )

Consequence

SIM1
NM_005068.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.45

Publications

31 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 links:

SIM1-AS1 (HGNC:40530): (SIM1 antisense RNA 1)

SIM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033548474).

BP6

Variant 6-100420845-G-A is Benign according to our data. Variant chr6-100420845-G-A is described in ClinVar as Benign. ClinVar VariationId is 354680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIM1	NM_005068.3	MANE Select	c.1112C>T	p.Ala371Val	missense	Exon 10 of 12	NP_005059.2
SIM1	NM_001374769.1		c.1112C>T	p.Ala371Val	missense	Exon 10 of 12	NP_001361698.1	P81133
SIM1-AS1	NR_187148.1		n.891-6273G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIM1	ENST00000369208.8	TSL:1 MANE Select	c.1112C>T	p.Ala371Val	missense	Exon 10 of 12	ENSP00000358210.4	P81133
SIM1	ENST00000262901.4	TSL:1	c.1112C>T	p.Ala371Val	missense	Exon 9 of 11	ENSP00000262901.4	P81133
SIM1	ENST00000900753.1		c.1112C>T	p.Ala371Val	missense	Exon 10 of 12	ENSP00000570812.1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19675

AN:

152026

Hom.:

1737

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.185

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.119

GnomAD2 exomes

AF:

0.178

AC:

44819

AN:

251222

AF XY:

0.176

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.430

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.152

AC:

221777

AN:

1461412

Hom.:

19904

Cov.:

AF XY:

0.152

AC XY:

110561

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.0237

AC:

794

AN:

33478

American (AMR)

AF:

0.255

AC:

11416

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3239

AN:

26132

East Asian (EAS)

AF:

0.465

AC:

18442

AN:

39686

South Asian (SAS)

AF:

0.166

AC:

14304

AN:

86250

European-Finnish (FIN)

AF:

0.183

AC:

9769

AN:

53402

Middle Eastern (MID)

AF:

0.114

AC:

659

AN:

5766

European-Non Finnish (NFE)

AF:

0.139

AC:

154246

AN:

1111618

Other (OTH)

AF:

0.148

AC:

8908

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

10577

21154

31730

42307

52884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5634

11268

16902

22536

28170

<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:

0.129

AC:

19697

AN:

152144

Hom.:

1742

Cov.:

AF XY:

0.135

AC XY:

10065

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0296

AC:

1230

AN:

41544

American (AMR)

AF:

0.195

AC:

2984

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

426

AN:

3472

East Asian (EAS)

AF:

0.427

AC:

2202

AN:

5152

South Asian (SAS)

AF:

0.175

AC:

844

AN:

4810

European-Finnish (FIN)

AF:

0.185

AC:

1958

AN:

10580

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9650

AN:

68004

Other (OTH)

AF:

0.119

AC:

251

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

802

1605

2407

3210

4012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.138

Hom.:

4361

Bravo

AF:

0.127

TwinsUK

AF:

0.140

AC:

519

ALSPAC

AF:

0.124

AC:

478

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.136

AC:

1172

ExAC

AF:

0.172

AC:

20830

Asia WGS

AF:

0.253

AC:

877

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.135

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Obesity due to SIM1 deficiency (1)

SIM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.5

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.39

REVEL

Benign

0.047

Sift

Benign

0.56

Sift4G

Benign

0.32

Polyphen

0.0030

Vest4

0.025

MPC

0.026

ClinPred

0.0044

GERP RS

2.9

Varity_R

0.032

gMVP

0.20

Mutation Taster

=96/4

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over