21-31667461-TAA-TA

Variant names:

• chr21-31667461-TA-T
• rs3216079
• NM_000454.5:c.357+89delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000454.5(SOD1):​c.357+89delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,001,226 control chromosomes in the GnomAD database, including 13,009 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1977 hom., cov: 31)
  • Exomes 𝑓: 0.11 (11032 hom.)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.213
• Publications: 6 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

ENSG00000273271 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.357+89delA		intron_variant	Intron 4 of 4	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.357+87delA		intron_variant	Intron 4 of 4	1	NM_000454.5	ENSP00000270142.7

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19335 AN: 152108 Hom.: 1972 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.108 AC: 92018 AN: 849000 Hom.: 11032 AF XY: 0.108 AC XY: 48093 AN XY: 447324

African (AFR) AF: 0.174 AC: 3774 AN: 21674

American (AMR) AF: 0.328 AC: 14418 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1570 AN: 22250

East Asian (EAS) AF: 0.524 AC: 19284 AN: 36830

South Asian (SAS) AF: 0.187 AC: 13774 AN: 73574

European-Finnish (FIN) AF: 0.0932 AC: 4712 AN: 50564

Middle Eastern (MID) AF: 0.0637 AC: 263 AN: 4126

European-Non Finnish (NFE) AF: 0.0534 AC: 29707 AN: 555896

Other (OTH) AF: 0.112 AC: 4516 AN: 40168

GnomAD4 genome AF: 0.127 AC: 19367 AN: 152226 Hom.: 1977 Cov.: 31 AF XY: 0.132 AC XY: 9843 AN XY: 74444

African (AFR) AF: 0.178 AC: 7387 AN: 41518

American (AMR) AF: 0.202 AC: 3081 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3468

East Asian (EAS) AF: 0.514 AC: 2659 AN: 5170

South Asian (SAS) AF: 0.207 AC: 999 AN: 4826

European-Finnish (FIN) AF: 0.0960 AC: 1019 AN: 10616

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0547 AC: 3719 AN: 68018

Other (OTH) AF: 0.107 AC: 226 AN: 2114

Alfa AF: 0.0146 Hom.: 6

Bravo AF: 0.140

Asia WGS AF: 0.330 AC: 1147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21
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: rs3216079; hg19: chr21-33039774;