9-34637606-C-G

Variant names:

• chr9-34637606-C-G
• rs532632647
• NM_005866.4:c.92G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001282207.2(SIGMAR1):​c.91+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIGMAR1 NM_001282207.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 1 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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282207.2. 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.92G>C	p.Gly31Ala	missense	Exon 1 of 4	NP_005857.1	Q99720-1
	SIGMAR1	NM_147157.3		c.92G>C	p.Gly31Ala	missense	Exon 1 of 3	NP_671513.1	Q99720-3
	SIGMAR1	NM_001282208.2		c.92G>C	p.Gly31Ala	missense	Exon 1 of 4	NP_001269137.1	A0A7P0Z4C2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.92G>C	p.Gly31Ala	missense	Exon 1 of 4	ENSP00000277010.4	Q99720-1
	SIGMAR1	ENST00000477726.1	TSL:1	c.92G>C	p.Gly31Ala	missense	Exon 1 of 3	ENSP00000420022.1	Q99720-3
	SIGMAR1	ENST00000353468.4	TSL:1	n.92G>C		non_coding_transcript_exon	Exon 1 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 157682 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 694540

African (AFR) AF: 0.00 AC: 0 AN: 32106

American (AMR) AF: 0.00 AC: 0 AN: 38300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 36658

South Asian (SAS) AF: 0.00 AC: 0 AN: 80624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087692

Other (OTH) AF: 0.00 AC: 0 AN: 58438

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000172 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.068
Sift	Benign	0.36	T
Sift4G	Benign	0.81	T
Polyphen		0.0090	B
Vest4		0.11
MutPred		0.56		Loss of loop (P = 0.0031)
MVP		0.48
MPC		0.87
ClinPred		0.65	D
GERP RS		3.7
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.74
Mutation Taster		=72/28	polymorphism

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: rs532632647; hg19: chr9-34637603;