rs2073417

Variant names:

• chr21-36748417-G-A
• rs2073417
• NM_005069.6:c.*325G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005069.6(SIM2):​c.*325G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 157,394 control chromosomes in the GnomAD database, including 5,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (5780 hom., cov: 33)
  • Exomes 𝑓: 0.25 (182 hom.)
• Consequence: SIM2 NM_005069.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980

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]

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM2	NM_005069.6	c.*325G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000290399.11	NP_005060.1
HLCS	NM_001352514.2	c.*5829C>T		downstream_gene_variant		ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.*325G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_005069.6	ENSP00000290399.6
HLCS	ENST00000674895.3	c.*5829C>T		downstream_gene_variant			NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40481 AN: 152038 Hom.: 5771 Cov.: 33

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.246 AC: 1289 AN: 5238 Hom.: 182 Cov.: 0 AF XY: 0.239 AC XY: 651 AN XY: 2728

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.391

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.266 AC: 40511 AN: 152156 Hom.: 5780 Cov.: 33 AF XY: 0.265 AC XY: 19676 AN XY: 74380

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.273

Alfa AF: 0.236 Hom.: 5522

Bravo AF: 0.271

Asia WGS AF: 0.271 AC: 941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.80

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

Other links and lift over

dbSNP: rs2073417; hg19: chr21-38120718;