rs3734355

chr6-100420845-G-Achr6-100420845-G-Cchr6-100420845-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005068.3(SIM1):c.1112C>T(p.Ala371Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,556 control chromosomes in the GnomAD database, including 21,646 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1742 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19904 hom.)
• Consequence: SIM1 NM_005068.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.45

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033548474).
• BP6: Variant 6-100420845-G-A is Benign according to our data. Variant chr6-100420845-G-A is described in ClinVar as [Benign]. Clinvar id is 354680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM1	NM_005068.3	c.1112C>T	p.Ala371Val	missense_variant	10/12	ENST00000369208.8
SIM1-AS1	XR_942815.4	n.891-6273G>A		intron_variant, non_coding_transcript_variant
SIM1	NM_001374769.1	c.1112C>T	p.Ala371Val	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM1	ENST00000369208.8	c.1112C>T	p.Ala371Val	missense_variant	10/12	1	NM_005068.3	P1
SIM1	ENST00000262901.4	c.1112C>T	p.Ala371Val	missense_variant	9/11	1		P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19675 AN: 152026 Hom.: 1737 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.178 AC: 44819 AN: 251222 Hom.: 5209 AF XY: 0.176 AC XY: 23866 AN XY: 135780

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.152 AC: 221777 AN: 1461412 Hom.: 19904 Cov.: 33 AF XY: 0.152 AC XY: 110561 AN XY: 727018

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.129 AC: 19697 AN: 152144 Hom.: 1742 Cov.: 32 AF XY: 0.135 AC XY: 10065 AN XY: 74366

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.119

Alfa AF: 0.140 Hom.: 2880

Bravo AF: 0.127

TwinsUK AF: 0.140 AC: 519

ALSPAC AF: 0.124 AC: 478

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.136 AC: 1172

ExAC AF: 0.172 AC: 20830

Asia WGS AF: 0.253 AC: 877 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 16924270) -

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. -

SIM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.81	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.047
Sift	Benign	0.56	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0030	B;B
Vest4		0.025
MPC		0.026
ClinPred		0.0044	T
GERP RS		2.9
Varity_R		0.032
gMVP		0.20

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

Other links and lift over

dbSNP: rs3734355; hg19: chr6-100868721; COSMIC: COSV53490167;