rs1041740

Variant names:

• chr21-31667849-C-T
• rs1041740
• NM_000454.5:c.357+474C>T

Variant summary

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

The NM_000454.5(SOD1):​c.357+474C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,118 control chromosomes in the GnomAD database, including 5,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (5471 hom., cov: 32)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.455
• Publications: 48 publications found

Genes affected

SOD1 (HGNC:11179): (superoxide dismutase 1) The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally-occuring but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. In addition, this protein contains an antimicrobial peptide that displays antibacterial, antifungal, and anti-MRSA activity against E. coli, E. faecalis, S. aureus, S. aureus MRSA LPV+, S. agalactiae, and yeast C. krusei. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene. [provided by RefSeq, Jul 2020]

SOD1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic tetraplegia and axial hypotonia, progressive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD 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=-0.82).
• BP6: Variant 21-31667849-C-T is Benign according to our data. Variant chr21-31667849-C-T is described in ClinVar as Benign. ClinVar VariationId is 1261166.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000454.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.357+474C>T		intron	N/A	NP_000445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.357+474C>T		intron	N/A	ENSP00000270142.7
	SOD1	ENST00000389995.4	TSL:3	c.300+474C>T		intron	N/A	ENSP00000374645.4
	SOD1	ENST00000470944.1	TSL:2	n.1285+474C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37857 AN: 152000 Hom.: 5466 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.249 AC: 37858 AN: 152118 Hom.: 5471 Cov.: 32 AF XY: 0.251 AC XY: 18637 AN XY: 74348

African (AFR) AF: 0.0999 AC: 4152 AN: 41554

American (AMR) AF: 0.309 AC: 4720 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1464 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1664 AN: 5170

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4822

European-Finnish (FIN) AF: 0.234 AC: 2472 AN: 10566

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20687 AN: 67956

Other (OTH) AF: 0.283 AC: 598 AN: 2112

Alfa AF: 0.290 Hom.: 28661

Bravo AF: 0.250

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.26
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs1041740; hg19: chr21-33040162;