rs147054081

Variant names:

• chr21-36719859-T-A
• rs147054081
• 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. The variant received 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. Synonymous variant affecting the same amino acid position (i.e. H129H) has been classified as Benign.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005069.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	NM_005069.6	MANE Select	c.387T>A	p.His129Gln	missense	Exon 4 of 11	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.387T>A	p.His129Gln	missense	Exon 4 of 10	NP_033664.2	Q14190-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.387T>A	p.His129Gln	missense	Exon 4 of 11	ENSP00000290399.6	Q14190-1
	SIM2	ENST00000431229.1	TSL:1	c.198T>A	p.His66Gln	missense	Exon 3 of 10	ENSP00000392003.1	H7BZX8
	SIM2	ENST00000483178.2	TSL:3	c.96T>A	p.His32Gln	missense	Exon 2 of 2	ENSP00000476273.1	V9GY04

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		-1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	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
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs147054081; hg19: chr21-38092160;