Genetic Variant SIM1:c.*1601T>A (chr6-100388760-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005068.3(SIM1):c.*1601T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,124 control chromosomes in the GnomAD database, including 4,294 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.21 ( 4294 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

SIM1
NM_005068.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3 link	c.*1601T>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1 link	c.*1601T>A		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.*1601T>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4 link	c.*1601T>A		downstream_gene_variant		1		ENSP00000262901.4

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31465

AN:

152006

Hom.:

4287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0554

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.266

Gnomad FIN

AF:

0.320

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.192

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.207

AC:

31483

AN:

152124

Hom.:

4294

Cov.:

AF XY:

0.215

AC XY:

16005

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0555

AC:

2305

AN:

41546

American (AMR)

AF:

0.283

AC:

4327

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3470

East Asian (EAS)

AF:

0.594

AC:

3074

AN:

5174

South Asian (SAS)

AF:

0.265

AC:

1277

AN:

4810

European-Finnish (FIN)

AF:

0.320

AC:

3379

AN:

10572

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15847

AN:

67962

Other (OTH)

AF:

0.191

AC:

403

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1186

2373

3559

4746

5932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.217

Hom.:

470

Bravo

AF:

0.201

Asia WGS

AF:

0.360

AC:

1250

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.7

(source)

DANN

Benign

0.77

PhyloP100

1.6

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over