Genetic Variant SIM1:c.998+4153T>C (chr6-100443115-A-G) – 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.998+4153T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,658 control chromosomes in the GnomAD database, including 13,595 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 0.40 ( 13595 hom., cov: 32)

Consequence

SIM1
NM_005068.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.120

Publications

3 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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 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.998+4153T>C	intron	N/A	NP_005059.2
SIM1	NM_001374769.1		c.998+4153T>C	intron	N/A	NP_001361698.1	P81133
SIM1-AS1	NR_187148.1		n.6901A>G	non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SIM1	ENST00000369208.8	TSL:1 MANE Select	c.998+4153T>C	intron	N/A	ENSP00000358210.4	P81133
SIM1	ENST00000262901.4	TSL:1	c.998+4153T>C	intron	N/A	ENSP00000262901.4	P81133
SIM1	ENST00000900753.1		c.998+4153T>C	intron	N/A	ENSP00000570812.1

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61255

AN:

151540

Hom.:

13569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.574

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.461

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.592

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.340

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.355

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

GnomAD4 genome

AF:

0.404

AC:

61328

AN:

151658

Hom.:

13595

Cov.:

AF XY:

0.408

AC XY:

30232

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.574

AC:

23752

AN:

41386

American (AMR)

AF:

0.461

AC:

7027

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

834

AN:

3462

East Asian (EAS)

AF:

0.591

AC:

3041

AN:

5146

South Asian (SAS)

AF:

0.288

AC:

1383

AN:

4802

European-Finnish (FIN)

AF:

0.340

AC:

3584

AN:

10540

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.303

AC:

20563

AN:

67768

Other (OTH)

AF:

0.351

AC:

741

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1701

3403

5104

6806

8507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.343

Hom.:

1609

Bravo

AF:

0.426

Asia WGS

AF:

0.437

AC:

1513

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

8.0

(source)

DANN

Benign

0.78

PhyloP100

0.12

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