21-31660675-C-A

Variant names:

• chr21-31660675-C-A
• rs6650814
• NM_000454.5:c.72+834C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000454.5(SOD1):​c.72+834C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,202 control chromosomes in the GnomAD database, including 1,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1691 hom., cov: 33)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.72+834C>A		intron_variant	Intron 1 of 4	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.72+834C>A		intron_variant	Intron 1 of 4	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000470944.1	n.967C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2
SOD1	ENST00000389995.4	c.15+891C>A		intron_variant	Intron 1 of 4	3		ENSP00000374645.4
SOD1	ENST00000476106.5	n.149+834C>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16524 AN: 152070 Hom.: 1673 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0940

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0741

GnomAD4 exome AF: 0.0714 AC: 1 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.109 AC: 16588 AN: 152188 Hom.: 1691 Cov.: 33 AF XY: 0.107 AC XY: 7933 AN XY: 74434

African (AFR) AF: 0.271 AC: 11236 AN: 41478

American (AMR) AF: 0.0487 AC: 745 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4832

European-Finnish (FIN) AF: 0.0940 AC: 997 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3277 AN: 68014

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.0477 Hom.: 81

Bravo AF: 0.114

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-0.35
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: rs6650814; hg19: chr21-33032988;