Genetic Variant SIGMAR1:p.Ser101Ser (chr9-34637269-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001282206.2(SIGMAR1):c.50C>A(p.Pro17Gln) variant causes a missense, splice region 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. 5/6 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P17L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIGMAR1
NM_001282206.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.117

Publications

1 publications found

Variant links:

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 links:

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

GALT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282206.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIGMAR1	NM_005866.4	MANE Select	c.303C>A	p.Ser101Ser	synonymous	Exon 2 of 4	NP_005857.1	Q99720-1
SIGMAR1	NM_001282206.2		c.50C>A	p.Pro17Gln	missense splice_region	Exon 2 of 4	NP_001269135.1
SIGMAR1	NM_001282207.2		c.243C>A	p.Ser81Ser	synonymous	Exon 2 of 4	NP_001269136.1	Q99720-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.303C>A	p.Ser101Ser	synonymous	Exon 2 of 4	ENSP00000277010.4	Q99720-1
SIGMAR1	ENST00000477726.1	TSL:1	c.303C>A	p.Ser101Ser	synonymous	Exon 2 of 3	ENSP00000420022.1	Q99720-3
SIGMAR1	ENST00000353468.4	TSL:1	n.303C>A		splice_region non_coding_transcript_exon	Exon 2 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1420484

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704280

African (AFR)

AF:

0.00

AC:

AN:

32836

American (AMR)

AF:

0.00

AC:

AN:

39470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25516

East Asian (EAS)

AF:

0.00

AC:

AN:

37978

South Asian (SAS)

AF:

0.00

AC:

AN:

82544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095610

Other (OTH)

AF:

0.00

AC:

AN:

59120

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

0.12

PromoterAI

-0.045

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over