rs1799729

Variant names:

• chr9-34637993-G-A
• rs1799729
• ENST00000902330.1:c.-29+181G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000902330.1(GALT):​c.-29+181G>A variant causes a intron 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: GALT ENST00000902330.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170
• Publications: 6 publications found

Genes affected

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]

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]

SIGMAR1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal recessive distal spinal muscular atrophy 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000902330.1. 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.-296C>T		upstream_gene	N/A	NP_005857.1	Q99720-1
	SIGMAR1	NM_001282207.2		c.-296C>T		upstream_gene	N/A	NP_001269136.1	Q99720-2
	SIGMAR1	NM_147157.3		c.-296C>T		upstream_gene	N/A	NP_671513.1	Q99720-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	ENST00000902330.1		c.-29+181G>A		intron	N/A	ENSP00000572389.1
	GALT	ENST00000902331.1		c.-127+181G>A		intron	N/A	ENSP00000572390.1
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.-296C>T		upstream_gene	N/A	ENSP00000277010.4	Q99720-1

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

African (AFR) AF: 0.155 AC: 922 AN: 5938

American (AMR) AF: 0.231 AC: 1388 AN: 6010

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1100 AN: 8552

East Asian (EAS) AF: 0.295 AC: 5372 AN: 18200

South Asian (SAS) AF: 0.142 AC: 1537 AN: 10802

European-Finnish (FIN) AF: 0.109 AC: 2402 AN: 21992

Middle Eastern (MID) AF: 0.159 AC: 202 AN: 1272

European-Non Finnish (NFE) AF: 0.148 AC: 23700 AN: 160322

Other (OTH) AF: 0.156 AC: 2538 AN: 16220

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

African (AFR) AF: 0.162 AC: 6735 AN: 41554

American (AMR) AF: 0.222 AC: 3395 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1591 AN: 5162

South Asian (SAS) AF: 0.191 AC: 922 AN: 4828

European-Finnish (FIN) AF: 0.120 AC: 1272 AN: 10612

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10964 AN: 68000

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.171 Hom.: 1029

Bravo AF: 0.181

Asia WGS AF: 0.252 AC: 878 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.7
DANN	Benign	0.68
PhyloP100		-0.017
PromoterAI		-0.027	Neutral

Splicing

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

Other links and lift over

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