rs147054081

Variant names:

• chr21-36719859-T-A
• NM_005069.6:c.387T>A

Your query was ambiguous. Multiple possible variants found:

• chr21-36719859-T-A
• chr21-36719859-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005069.6(SIM2):​c.387T>A​(p.His129Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIM2 NM_005069.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM2	NM_005069.6	c.387T>A	p.His129Gln	missense_variant	Exon 4 of 11	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.387T>A	p.His129Gln	missense_variant	Exon 4 of 11	1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000431229.1	c.198T>A	p.His66Gln	missense_variant	Exon 3 of 10	1		ENSP00000392003.1
SIM2	ENST00000483178.2	c.96T>A	p.His32Gln	missense_variant	Exon 2 of 2	3		ENSP00000476273.1
SIM2	ENST00000481185.1	n.1000T>A		non_coding_transcript_exon_variant	Exon 4 of 10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461248 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.49	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.87		Loss of disorder (P = 0.1309);.;
MVP		0.43
MPC		1.0
ClinPred		1.0	D
GERP RS		-2.9
Varity_R		0.90
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38092160;