NM_000454.5:c.170-1280A>T

Variant names:

• chr21-31665169-A-T
• rs9967983
• NM_000454.5:c.170-1280A>T

Variant summary

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

The NM_000454.5(SOD1):​c.170-1280A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 151,484 control chromosomes in the GnomAD database, including 17,749 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 0.48 (17749 hom., cov: 29)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.59
• Publications: 4 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.170-1280A>T		intron_variant	Intron 2 of 4	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.170-1280A>T		intron_variant	Intron 2 of 4	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000389995.4	c.113-1280A>T		intron_variant	Intron 2 of 4	3		ENSP00000374645.4
SOD1	ENST00000470944.1	n.1098-1280A>T		intron_variant	Intron 2 of 4	2
SOD1	ENST00000476106.5	n.433-1280A>T		intron_variant	Intron 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72295 AN: 151366 Hom.: 17728 Cov.: 29

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.465

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

GnomAD4 genome AF: 0.478 AC: 72361 AN: 151484 Hom.: 17749 Cov.: 29 AF XY: 0.482 AC XY: 35690 AN XY: 74012

African (AFR) AF: 0.495 AC: 20402 AN: 41224

American (AMR) AF: 0.558 AC: 8493 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1815 AN: 3466

East Asian (EAS) AF: 0.809 AC: 4133 AN: 5110

South Asian (SAS) AF: 0.541 AC: 2595 AN: 4794

European-Finnish (FIN) AF: 0.434 AC: 4554 AN: 10498

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.423 AC: 28682 AN: 67874

Other (OTH) AF: 0.467 AC: 981 AN: 2100

Alfa AF: 0.436 Hom.: 1840

Bravo AF: 0.492

Asia WGS AF: 0.622 AC: 2164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.018
DANN	Benign	0.31
PhyloP100		-5.6
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: rs9967983; hg19: chr21-33037482;