6-100420903-G-T

Variant names:

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.1054C>A(p.Pro352Thr) variant causes a missense change. The variant allele was found at a frequency of 0.15 in 1,613,500 control chromosomes in the GnomAD database, including 21,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1745 hom., cov: 32)

Exomes 𝑓: 0.15 ( 19892 hom. )

Consequence

SIM1
NM_005068.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.19

Publications

37 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=0.0011030436).

BP6

Variant 6-100420903-G-T is Benign according to our data. Variant chr6-100420903-G-T is described in ClinVar as Benign. ClinVar VariationId is 354681.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SIM1	NM_005068.3 link	c.1054C>A	p.Pro352Thr	missense_variant	Exon 10 of 12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1 link	c.1054C>A	p.Pro352Thr	missense_variant	Exon 10 of 12		NP_001361698.1
SIM1-AS1	NR_187148.1 link	n.891-6215G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8 link	c.1054C>A	p.Pro352Thr	missense_variant	Exon 10 of 12	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4 link	c.1054C>A	p.Pro352Thr	missense_variant	Exon 9 of 11	1		ENSP00000262901.4

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19651

AN:

151968

Hom.:

1741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.175

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:

44702

AN:

250782

AF XY:

0.176

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.431

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.152

AC:

221787

AN:

1461414

Hom.:

19892

Cov.:

AF XY:

0.152

AC XY:

110559

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.0227

AC:

761

AN:

33478

American (AMR)

AF:

0.255

AC:

11395

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3241

AN:

26134

East Asian (EAS)

AF:

0.465

AC:

18446

AN:

39680

South Asian (SAS)

AF:

0.166

AC:

14304

AN:

86236

European-Finnish (FIN)

AF:

0.183

AC:

9765

AN:

53398

Middle Eastern (MID)

AF:

0.114

AC:

657

AN:

5764

European-Non Finnish (NFE)

AF:

0.139

AC:

154325

AN:

1111692

Other (OTH)

AF:

0.147

AC:

8893

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

10322

20644

30966

41288

51610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5640

11280

16920

22560

28200

<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:

19665

AN:

152086

Hom.:

1745

Cov.:

AF XY:

0.135

AC XY:

10048

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0287

AC:

1193

AN:

41514

American (AMR)

AF:

0.195

AC:

2985

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

426

AN:

3470

East Asian (EAS)

AF:

0.428

AC:

2203

AN:

5146

South Asian (SAS)

AF:

0.175

AC:

842

AN:

4814

European-Finnish (FIN)

AF:

0.185

AC:

1959

AN:

10580

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9653

AN:

67972

Other (OTH)

AF:

0.119

AC:

252

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

820

1640

2460

3280

4100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.141

Hom.:

6066

Bravo

AF:

0.127

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.123

AC:

475

ESP6500AA

AF:

0.0313

AC:

138

ESP6500EA

AF:

0.136

AC:

1171

ExAC

AF:

0.171

AC:

20800

Asia WGS

AF:

0.252

AC:

872

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.135

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16924270) -

Obesity due to SIM1 deficiency

Benign:1

Jan 13, 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

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N

PhyloP100

6.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.40

T;T

Polyphen

0.052

B;B

Vest4

0.11

MPC

0.037

ClinPred

0.016

GERP RS

5.8

Varity_R

0.13

gMVP

0.34

Mutation Taster

=80/20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over