21-36723048-A-G

Variant names:

• chr21-36723048-A-G
• rs201840539
• NM_005069.6:c.461A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.54

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]

ACMG classification

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 rank	MANE	Protein	UniProt
SIM2	NM_005069.6	c.461A>G	p.Tyr154Cys	missense_variant	Exon 5 of 11	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.461A>G	p.Tyr154Cys	missense_variant	Exon 5 of 11	1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000431229.1	c.272A>G	p.Tyr91Cys	missense_variant	Exon 4 of 10	1		ENSP00000392003.1
SIM2	ENST00000481185.1	n.1074A>G		non_coding_transcript_exon_variant	Exon 5 of 10	2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 32

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: 13 AN: 251426 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135898

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: 44 AN: 1461596 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 727140

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: 11 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

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.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.025	D
Sift4G	Benign	0.063	T
Polyphen		0.73	P
Vest4		0.74
MVP		0.88
MPC		0.54
ClinPred		0.38	T
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

Other links and lift over

dbSNP: rs201840539; hg19: chr21-38095349;