rs1554707622

Variant names:

• chr9-34635591-CGCTCCTGTCTATCCGCAGGTCTTCCTTCAGGCCTGGCTGGTCAAGGGTCCTGGCCAAAGAGGTAGGTGGTGAGCTCAAGCCGGAGGCCCCGAGCATAGGAGCGAAGAGTATAGAAGAGGGTGAGGAAGTCCTGGGTGCTGAAGACAGTGTCGGCCAGCGCGAAGGCCAGGGTGGATGGGATGACGCCCCGGCCGTACTCCACCATCCATGTGTTTGGCCCCCACTCCACAGCTGTTGCCTCACCAGGCCCGTGTACTACCGTCTCCCCTGGGGGACAGGGAGCACCCAAGTG-C
• rs1554707622
• NM_005866.4:c.446-25_*40del

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_005866.4(SIGMAR1):​c.446-25_*40del​(p.Gly149_Ter224delins???) variant causes a stop lost, conservative inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGMAR1 NM_005866.4 stop_lost, conservative_inframe_deletion, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.30
• Publications: 0 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]

SIGMAR1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_005866.4
• PM4: Stoplost variant in NM_005866.4
• PP5: Variant 9-34635591-CGCTCCTGTCTATCCGCAGGTCTTCCTTCAGGCCTGGCTGGTCAAGGGTCCTGGCCAAAGAGGTAGGTGGTGAGCTCAAGCCGGAGGCCCCGAGCATAGGAGCGAAGAGTATAGAAGAGGGTGAGGAAGTCCTGGGTGCTGAAGACAGTGTCGGCCAGCGCGAAGGCCAGGGTGGATGGGATGACGCCCCGGCCGTACTCCACCATCCATGTGTTTGGCCCCCACTCCACAGCTGTTGCCTCACCAGGCCCGTGTACTACCGTCTCCCCTGGGGGACAGGGAGCACCCAAGTG-C is Pathogenic according to our data. Variant chr9-34635591-CGCTCCTGTCTATCCGCAGGTCTTCCTTCAGGCCTGGCTGGTCAAGGGTCCTGGCCAAAGAGGTAGGTGGTGAGCTCAAGCCGGAGGCCCCGAGCATAGGAGCGAAGAGTATAGAAGAGGGTGAGGAAGTCCTGGGTGCTGAAGACAGTGTCGGCCAGCGCGAAGGCCAGGGTGGATGGGATGACGCCCCGGCCGTACTCCACCATCCATGTGTTTGGCCCCCACTCCACAGCTGTTGCCTCACCAGGCCCGTGTACTACCGTCTCCCCTGGGGGACAGGGAGCACCCAAGTG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431074.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGMAR1	NM_005866.4	c.446-25_*40del	p.Gly149_Ter224delins???	stop_lost, conservative_inframe_deletion, splice_region_variant	Exon 4 of 4	ENST00000277010.9	NP_005857.1
SIGMAR1	NM_005866.4	c.446-25_*40del		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 4 of 4	ENST00000277010.9	NP_005857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.446-25_*40del	p.Gly149_Ter224delins???	stop_lost, conservative_inframe_deletion, splice_region_variant	Exon 4 of 4	1	NM_005866.4	ENSP00000277010.4
SIGMAR1	ENST00000277010.9	c.446-25_*40del		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 4 of 4	1	NM_005866.4	ENSP00000277010.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 16 Pathogenic:1

-

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3

Splicing

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

Other links and lift over

dbSNP: rs1554707622; hg19: chr9-34635588;