Variant 6-100389986-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005068.3(SIM1):c.*375C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 381,984 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

SIM1
NM_005068.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.18

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=-0.85).

BP6

Variant 6-100389986-G-A is Benign according to our data. Variant chr6-100389986-G-A is described in ClinVar as [Benign]. Clinvar id is 354669.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1653/152132) while in subpopulation AFR AF= 0.0382 (1587/41500). AF 95% confidence interval is 0.0367. There are 35 homozygotes in gnomad4. There are 795 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1653 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM1	NM_005068.3 linkuse as main transcript	c.*375C>T		3_prime_UTR_variant	12/12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1 linkuse as main transcript	c.*375C>T		3_prime_UTR_variant	12/12		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8 linkuse as main transcript	c.*375C>T		3_prime_UTR_variant	12/12	1	NM_005068.3	ENSP00000358210	P1
SIM1	ENST00000262901.4 linkuse as main transcript	c.*375C>T		3_prime_UTR_variant	11/11	1		ENSP00000262901	P1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1648

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0382

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00860

GnomAD4 exome

AF:

0.00154

AC:

354

AN:

229852

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

139

AN XY:

117002

show subpopulations

Gnomad4 AFR exome

AF:

0.0385

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000479

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000542

Gnomad4 OTH exome

AF:

0.00415

GnomAD4 genome

AF:

0.0109

AC:

1653

AN:

152132

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

795

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0382

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Obesity due to SIM1 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.5

DANN

Benign

0.52

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