Genetic Variant SIM1:c.743+66A>C (chr6-100448413-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005068.3(SIM1):c.743+66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,518,488 control chromosomes in the GnomAD database, including 56,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.26 ( 5383 hom., cov: 33)

Exomes 𝑓: 0.27 ( 51297 hom. )

Consequence

SIM1
NM_005068.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.336

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 6-100448413-T-G is Benign according to our data. Variant chr6-100448413-T-G is described in ClinVar as Benign. ClinVar VariationId is 1246330.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3 link	c.743+66A>C		intron_variant	Intron 7 of 11	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1 link	c.743+66A>C		intron_variant	Intron 7 of 11		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8 link	c.743+66A>C		intron_variant	Intron 7 of 11	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4 link	c.743+66A>C		intron_variant	Intron 6 of 10	1		ENSP00000262901.4

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39208

AN:

151998

Hom.:

5380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.325

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.264

Gnomad OTH

AF:

0.244

GnomAD4 exome

AF:

0.269

AC:

368171

AN:

1366372

Hom.:

51297

Cov.:

AF XY:

0.267

AC XY:

181044

AN XY:

677388

show subpopulations

African (AFR)

AF:

0.186

AC:

5795

AN:

31120

American (AMR)

AF:

0.405

AC:

15587

AN:

38534

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5111

AN:

24082

East Asian (EAS)

AF:

0.429

AC:

16002

AN:

37314

South Asian (SAS)

AF:

0.212

AC:

16905

AN:

79682

European-Finnish (FIN)

AF:

0.311

AC:

15766

AN:

50740

Middle Eastern (MID)

AF:

0.282

AC:

1299

AN:

4614

European-Non Finnish (NFE)

AF:

0.265

AC:

276591

AN:

1043562

Other (OTH)

AF:

0.266

AC:

15115

AN:

56724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

14000

28000

42001

56001

70001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9476

18952

28428

37904

47380

<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:

0.258

AC:

39227

AN:

152116

Hom.:

5383

Cov.:

AF XY:

0.263

AC XY:

19562

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.189

AC:

7863

AN:

41498

American (AMR)

AF:

0.348

AC:

5319

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

711

AN:

3468

East Asian (EAS)

AF:

0.400

AC:

2065

AN:

5166

South Asian (SAS)

AF:

0.212

AC:

1022

AN:

4820

European-Finnish (FIN)

AF:

0.323

AC:

3406

AN:

10560

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.264

AC:

17953

AN:

67994

Other (OTH)

AF:

0.241

AC:

510

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1528

3056

4583

6111

7639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.254

Hom.:

826

Bravo

AF:

0.262

Asia WGS

AF:

0.280

AC:

974

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.1

(source)

DANN

Benign

0.51

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over