Genetic Variant SIM1:c.743+112T>C (chr6-100448367-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005068.3(SIM1):c.743+112T>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 1,387,752 control chromosomes in the GnomAD database, including 51,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.26 ( 5343 hom., cov: 33)

Exomes 𝑓: 0.27 ( 46624 hom. )

Consequence

SIM1
NM_005068.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.91

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 6-100448367-A-G is Benign according to our data. Variant chr6-100448367-A-G is described in ClinVar as [Benign]. Clinvar id is 1273352.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+112T>C		intron_variant	Intron 7 of 11	ENST00000369208.8	NP_005059.2	P81133
SIM1	NM_001374769.1 link	c.743+112T>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+112T>C		intron_variant	Intron 7 of 11	1	NM_005068.3	ENSP00000358210.4		P81133
SIM1	ENST00000262901.4 link	c.743+112T>C		intron_variant	Intron 6 of 10	1		ENSP00000262901.4		P81133

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39030

AN:

152014

Hom.:

5342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.325

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.244

GnomAD4 exome

AF:

0.270

AC:

333011

AN:

1235620

Hom.:

46624

Cov.:

AF XY:

0.267

AC XY:

163793

AN XY:

613188

show subpopulations

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.399

Gnomad4 ASJ exome

AF:

0.211

Gnomad4 EAS exome

AF:

0.431

Gnomad4 SAS exome

AF:

0.211

Gnomad4 FIN exome

AF:

0.310

Gnomad4 NFE exome

AF:

0.265

Gnomad4 OTH exome

AF:

0.266

GnomAD4 genome

AF:

0.257

AC:

39043

AN:

152132

Hom.:

5343

Cov.:

AF XY:

0.262

AC XY:

19457

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.185

Gnomad4 AMR

AF:

0.347

Gnomad4 ASJ

AF:

0.205

Gnomad4 EAS

AF:

0.400

Gnomad4 SAS

AF:

0.212

Gnomad4 FIN

AF:

0.322

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.242

Alfa

AF:

0.226

Hom.:

1787

Bravo

AF:

0.261

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

-0.90

CADD

Benign

0.013

DANN

Benign

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over