rs387906829

Variant names:

• chr9-34637268-C-G
• rs387906829
• NM_005866.4:c.304G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-34637268-C-G
• chr9-34637268-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_005866.4(SIGMAR1):​c.304G>C​(p.Glu102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002135104: Experimental studies have shown that this missense change affects SIGMAR1 function (PMID:21842496, 25175561, 25704016, 27821430, 28622300, 31696229)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIGMAR1 NM_005866.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.69
• Publications: 55 publications found

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]

GALT Gene-Disease associations (from GenCC):

• classic galactosemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• galactosemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002135104: Experimental studies have shown that this missense change affects SIGMAR1 function (PMID: 21842496, 25175561, 25704016, 27821430, 28622300, 31696229).; SCV002752915: Several functional studies demonstrate abnormal protein function including mislocalization, aggregation, impaired signaling and reduced cell survival (Al-Saif A et al. Ann Neurol, 2011 Dec;70:913-9; Fukunaga K et al. J Pharmacol Sci, 2015 Jan;127:36-41; Schmidt HR et al. Nature, 2016 Apr;532:527-30; Watanabe S et al. EMBO Mol Med, 2016 12;8:1421-1437; Dreser A et al. Cell Death Differ, 2017 10;24:1655-1671; Abramyan AM et al. Comput Struct Biotechnol J, 2020 Jan;18:199-206; Couly S et al. Hum Mol Genet, 2020 03;29:529-540; Rodríguez-Muñoz M et al. Int J Mol Sci, 2020 Oct;21:7339).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 9-34637268-C-G is Pathogenic according to our data. Variant chr9-34637268-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005866.4. 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
	SIGMAR1	NM_005866.4	MANE Select	c.304G>C	p.Glu102Gln	missense	Exon 2 of 4	NP_005857.1	Q99720-1
	SIGMAR1	NM_001282207.2		c.244G>C	p.Glu82Gln	missense	Exon 2 of 4	NP_001269136.1	Q99720-2
	SIGMAR1	NM_147157.3		c.304G>C	p.Glu102Gln	missense	Exon 2 of 3	NP_671513.1	Q99720-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.304G>C	p.Glu102Gln	missense	Exon 2 of 4	ENSP00000277010.4	Q99720-1
	SIGMAR1	ENST00000477726.1	TSL:1	c.304G>C	p.Glu102Gln	missense	Exon 2 of 3	ENSP00000420022.1	Q99720-3
	SIGMAR1	ENST00000353468.4	TSL:1	n.304G>C		splice_region non_coding_transcript_exon	Exon 2 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419908 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703908

African (AFR) AF: 0.00 AC: 0 AN: 32824

American (AMR) AF: 0.00 AC: 0 AN: 39352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 37920

South Asian (SAS) AF: 0.00 AC: 0 AN: 82546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095280

Other (OTH) AF: 0.00 AC: 0 AN: 59118

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Amyotrophic lateral sclerosis type 16 (1)
1	-	-	Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of sheet (P = 0.1158)
MVP		0.83
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.032	Neutral
Varity_R		0.98
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs387906829; hg19: chr9-34637265;