Genetic Variant SIM1:c.999-4423A>G (chr6-100425381-T-C) – 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.999-4423A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,162 control chromosomes in the GnomAD database, including 2,932 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 0.18 ( 2932 hom., cov: 32)

Consequence

SIM1
NM_005068.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.114

Publications

7 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:

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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=-0.74).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 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	Effect	Exon Rank	Protein	UniProt
SIM1	NM_005068.3	MANE Select	c.999-4423A>G	intron	N/A	NP_005059.2
SIM1	NM_001374769.1		c.999-4423A>G	intron	N/A	NP_001361698.1	P81133
SIM1-AS1	NR_187148.1		n.891-1737T>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SIM1	ENST00000369208.8	TSL:1 MANE Select	c.999-4423A>G	intron	N/A	ENSP00000358210.4	P81133
SIM1	ENST00000262901.4	TSL:1	c.999-4423A>G	intron	N/A	ENSP00000262901.4	P81133
SIM1	ENST00000900753.1		c.999-4423A>G	intron	N/A	ENSP00000570812.1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26602

AN:

152044

Hom.:

2924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0459

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.173

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.175

AC:

26633

AN:

152162

Hom.:

2932

Cov.:

AF XY:

0.180

AC XY:

13402

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0462

AC:

1921

AN:

41542

American (AMR)

AF:

0.229

AC:

3503

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

546

AN:

3470

East Asian (EAS)

AF:

0.433

AC:

2241

AN:

5174

South Asian (SAS)

AF:

0.225

AC:

1086

AN:

4830

European-Finnish (FIN)

AF:

0.254

AC:

2690

AN:

10572

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14047

AN:

67976

Other (OTH)

AF:

0.173

AC:

364

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1066

2132

3199

4265

5331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.147

Hom.:

613

Bravo

AF:

0.168

Asia WGS

AF:

0.273

AC:

947

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.2

(source)

DANN

Benign

0.75

PhyloP100

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over