Genetic Variant SIM1:c.*2222G>A (chr6-100388139-C-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.*2222G>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 0.323 in 151,858 control chromosomes in the GnomAD database, including 9,223 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 0.32 ( 9223 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

SIM1
NM_005068.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.391

Publications

2 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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3 link	c.*2222G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000369208.8	NP_005059.2	P81133
SIM1	NM_001374769.1 link	c.*2222G>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.*2222G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_005068.3	ENSP00000358210.4		P81133

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

49001

AN:

151742

Hom.:

9205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.298

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.745

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.317

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:

0.323

AC:

49038

AN:

151858

Hom.:

9223

Cov.:

AF XY:

0.329

AC XY:

24391

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.150

AC:

6236

AN:

41506

American (AMR)

AF:

0.417

AC:

6359

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1045

AN:

3466

East Asian (EAS)

AF:

0.746

AC:

3831

AN:

5134

South Asian (SAS)

AF:

0.337

AC:

1625

AN:

4824

European-Finnish (FIN)

AF:

0.404

AC:

4236

AN:

10490

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24636

AN:

67890

Other (OTH)

AF:

0.327

AC:

690

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1618

3235

4853

6470

8088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

500

1000

1500

2000

2500

<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:

0.336

Hom.:

1154

Bravo

AF:

0.320

Asia WGS

AF:

0.498

AC:

1727

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.93

(source)

DANN

Benign

0.39

PhyloP100

-0.39

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