dbSNP rs2073417: SIM2:c.*325G>A (chr21-36748417-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005069.6(SIM2):c.*325G>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 0.266 in 157,394 control chromosomes in the GnomAD database, including 5,962 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 0.27 ( 5780 hom., cov: 33)

Exomes 𝑓: 0.25 ( 182 hom. )

Consequence

SIM2
NM_005069.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0980

Publications

8 publications found

Variant links:

Genes affected

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

SIM2 links:

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

HLCS Gene-Disease associations (from GenCC):

holocarboxylase synthetase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

HLCS links:

Genome browser will be placed here

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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM2	NM_005069.6 link	c.*325G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000290399.11	NP_005060.1
HLCS	NM_001352514.2 link	c.*5829C>T		downstream_gene_variant		ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11 link	c.*325G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_005069.6	ENSP00000290399.6
HLCS	ENST00000674895.3 link	c.*5829C>T		downstream_gene_variant			NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40481

AN:

152038

Hom.:

5771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.367

Gnomad AMI

AF:

0.144

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.275

GnomAD4 exome

AF:

0.246

AC:

1289

AN:

5238

Hom.:

182

Cov.:

AF XY:

0.239

AC XY:

651

AN XY:

2728

show subpopulations

African (AFR)

AF:

0.313

AC:

AN:

198

American (AMR)

AF:

0.195

AC:

AN:

118

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

AN:

244

East Asian (EAS)

AF:

0.320

AC:

142

AN:

444

South Asian (SAS)

AF:

0.391

AC:

AN:

European-Finnish (FIN)

AF:

0.190

AC:

AN:

364

Middle Eastern (MID)

AF:

0.412

AC:

AN:

European-Non Finnish (NFE)

AF:

0.228

AC:

779

AN:

3412

Other (OTH)

AF:

0.262

AC:

AN:

378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.266

AC:

40511

AN:

152156

Hom.:

5780

Cov.:

AF XY:

0.265

AC XY:

19676

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.367

AC:

15253

AN:

41510

American (AMR)

AF:

0.222

AC:

3403

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1076

AN:

3470

East Asian (EAS)

AF:

0.232

AC:

1194

AN:

5154

South Asian (SAS)

AF:

0.291

AC:

1404

AN:

4826

European-Finnish (FIN)

AF:

0.187

AC:

1987

AN:

10602

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.226

AC:

15372

AN:

67984

Other (OTH)

AF:

0.273

AC:

576

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1559

3118

4677

6236

7795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.240

Hom.:

8003

Bravo

AF:

0.271

Asia WGS

AF:

0.271

AC:

941

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.6

(source)

DANN

Benign

0.80

PhyloP100

0.098

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over