6-100420903-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005068.3(SIM1):c.1054C>A(p.Pro352Thr) variant causes a missense change. The variant allele was found at a frequency of 0.15 in 1,613,500 control chromosomes in the GnomAD database, including 21,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1745 hom., cov: 32)

Exomes 𝑓: 0.15 ( 19892 hom. )

Consequence

SIM1
NM_005068.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.19

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:

SIM1-AS1 (HGNC:):

SIM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011030436).

BP6

Variant 6-100420903-G-T is Benign according to our data. Variant chr6-100420903-G-T is described in ClinVar as [Benign]. Clinvar id is 354681.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
SIM1	NM_005068.3 linkuse as main transcript	c.1054C>A	p.Pro352Thr	missense_variant	10/12	ENST00000369208.8
SIM1-AS1	XR_942815.4 linkuse as main transcript	n.891-6215G>T		intron_variant, non_coding_transcript_variant
SIM1	NM_001374769.1 linkuse as main transcript	c.1054C>A	p.Pro352Thr	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM1	ENST00000369208.8 linkuse as main transcript	c.1054C>A	p.Pro352Thr	missense_variant	10/12	1	NM_005068.3	P1
SIM1	ENST00000262901.4 linkuse as main transcript	c.1054C>A	p.Pro352Thr	missense_variant	9/11	1		P1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19651

AN:

151968

Hom.:

1741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.175

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:

44702

AN:

250782

Hom.:

5168

AF XY:

0.176

AC XY:

23807

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.431

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:

221787

AN:

1461414

Hom.:

19892

Cov.:

AF XY:

0.152

AC XY:

110559

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.0227

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:

0.147

GnomAD4 genome

AF:

0.129

AC:

19665

AN:

152086

Hom.:

1745

Cov.:

AF XY:

0.135

AC XY:

10048

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0287

Gnomad4 AMR

AF:

0.195

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.428

Gnomad4 SAS

AF:

0.175

Gnomad4 FIN

AF:

0.185

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.144

Hom.:

4192

Bravo

AF:

0.127

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.123

AC:

475

ESP6500AA

AF:

0.0313

AC:

138

ESP6500EA

AF:

0.136

AC:

1171

ExAC

AF:

0.171

AC:

20800

Asia WGS

AF:

0.252

AC:

872

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.135

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 13, 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

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.0000015

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.40

T;T

Polyphen

0.052

B;B

Vest4

0.11

MPC

0.037

ClinPred

0.016

GERP RS

5.8

Varity_R

0.13

gMVP

0.34

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