rs1799729

Variant names:

• chr9-34637993-G-A
• rs1799729
• NM_005866.4:c.-296C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005866.4(SIGMAR1):​c.-296C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 401,558 control chromosomes in the GnomAD database, including 5,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2248 hom., cov: 33)
  • Exomes 𝑓: 0.16 (3461 hom.)
• Consequence: SIGMAR1 NM_005866.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170

Genes affected

SIGMAR1 (HGNC:8157): (sigma non-opioid intracellular receptor 1) This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2013]

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-34637993-G-A is Benign according to our data. Variant chr9-34637993-G-A is described in ClinVar as [Benign]. Clinvar id is 1271335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGMAR1	NM_005866.4	c.-296C>T		upstream_gene_variant		ENST00000277010.9	NP_005857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.-296C>T		upstream_gene_variant		1	NM_005866.4	ENSP00000277010.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25977 AN: 152132 Hom.: 2249 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.157 AC: 39161 AN: 249308 Hom.: 3461 AF XY: 0.156 AC XY: 19808 AN XY: 127084

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.171 AC: 25977 AN: 152250 Hom.: 2248 Cov.: 33 AF XY: 0.171 AC XY: 12707 AN XY: 74446

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.181

Alfa AF: 0.162 Hom.: 388

Bravo AF: 0.181

Asia WGS AF: 0.252 AC: 878 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.7
DANN	Benign	0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1799729; hg19: chr9-34637990; COSMIC: COSV52844869;