Variant 21-36723048-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_005069.6(SIM2):c.461A>G(p.Tyr154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.54

Variant links:

Genes affected

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

SIM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-36723048-A-G is Pathogenic according to our data. Variant chr21-36723048-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334899.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM2	NM_005069.6 linkuse as main transcript	c.461A>G	p.Tyr154Cys	missense_variant	5/11	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11 linkuse as main transcript	c.461A>G	p.Tyr154Cys	missense_variant	5/11	1	NM_005069.6	ENSP00000290399	P1	Q14190-1
SIM2	ENST00000431229.1 linkuse as main transcript	c.275A>G	p.Tyr92Cys	missense_variant	4/10	1		ENSP00000392003
SIM2	ENST00000481185.1 linkuse as main transcript	n.1074A>G		non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251426

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000853

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neurodevelopmental with craniofacial anomalies disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

in vitro;in vivo;research

Human Genetics Section, Sidra Medicine

Dec 08, 2021

The Tyr154Cys homozygous missense variant in SIM2 was found by whole genome sequencing in a boy with multiple craniofacial anomalies, global developmental delay, and intellectual impairment. The identified variant is very rare (ExAC AF 2.47E-5, gnomAD AF 9.85E-5, GME AF 5.04E-4) and segregating in the family in an autosomal recessive inheritance. Both parents and two unaffected sisters were heterozygous for the variant, while the unaffected brother was homozygous for the reference allele. Additionally, functional studies on zebrafish showed that the Tyr154Cys variant caused craniofacial abnormalities mimicking the patient's phenotype. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.83

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.48

Sift

Uncertain

0.025

Sift4G

Benign

0.063

Polyphen

0.73

Vest4

0.74

MVP

0.88

MPC

0.54

ClinPred

0.38

GERP RS

5.1

Varity_R

0.42

gMVP

0.48

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

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