21-36748417-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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]

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]

HLCS Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	NM_005069.6	MANE Select	c.*325G>A		3_prime_UTR	Exon 11 of 11	NP_005060.1
	HLCS	NM_001352514.2	MANE Select	c.*5829C>T		downstream_gene	N/A	NP_001339443.1
	HLCS	NM_000411.8		c.*5829C>T		downstream_gene	N/A	NP_000402.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.*325G>A		3_prime_UTR	Exon 11 of 11	ENSP00000290399.6
	HLCS	ENST00000674895.3	MANE Select	c.*5829C>T		downstream_gene	N/A	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

African (AFR) AF: 0.313 AC: 62 AN: 198

American (AMR) AF: 0.195 AC: 23 AN: 118

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 83 AN: 244

East Asian (EAS) AF: 0.320 AC: 142 AN: 444

South Asian (SAS) AF: 0.391 AC: 18 AN: 46

European-Finnish (FIN) AF: 0.190 AC: 69 AN: 364

Middle Eastern (MID) AF: 0.412 AC: 14 AN: 34

European-Non Finnish (NFE) AF: 0.228 AC: 779 AN: 3412

Other (OTH) AF: 0.262 AC: 99 AN: 378

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

African (AFR) AF: 0.367 AC: 15253 AN: 41510

American (AMR) AF: 0.222 AC: 3403 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1076 AN: 3470

East Asian (EAS) AF: 0.232 AC: 1194 AN: 5154

South Asian (SAS) AF: 0.291 AC: 1404 AN: 4826

European-Finnish (FIN) AF: 0.187 AC: 1987 AN: 10602

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15372 AN: 67984

Other (OTH) AF: 0.273 AC: 576 AN: 2112

Alfa AF: 0.240 Hom.: 8003

Bravo AF: 0.271

Asia WGS AF: 0.271 AC: 941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.80
PhyloP100		0.098
Mutation Taster		=100/0	polymorphism (auto)

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: rs2073417; hg19: chr21-38120718;