21-31659777-C-T

Variant names:

• chr21-31659777-C-T
• rs1601153292
• NM_000454.5:c.8C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000454.5(SOD1):​c.8C>T​(p.Thr3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.117
• Publications: 1 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-DT (HGNC:55683): (SOD1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 96 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.83817 (below the threshold of 3.09). Trascript score misZ: 1.2198 (below the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 1, amyotrophic lateral sclerosis, spastic tetraplegia and axial hypotonia, progressive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2969797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 5	ENST00000270142.11	NP_000445.1
SOD1-DT	NR_187558.1	n.248G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 5	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000389995.4	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 5	3		ENSP00000374645.4
SOD1	ENST00000470944.1	n.69C>T		non_coding_transcript_exon_variant	Exon 1 of 5	2
SOD1	ENST00000476106.5	n.85C>T		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461546 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SOD1-related disorder Uncertain:1

Feb 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOD1 c.8C>T variant is predicted to result in the amino acid substitution p.Thr3Met. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0034	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Benign	-0.59	N;.
PhyloP100		-0.12
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.34	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.23	T;D
Sift4G	Benign	0.073	T;D
Polyphen		0.0	B;.
Vest4		0.077
MutPred		0.43		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.83
MPC		1.2
ClinPred		0.069	T
GERP RS		-0.61
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.75
Mutation Taster		=81/19	polymorphism

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: rs1601153292; hg19: chr21-33032090; COSMIC: COSV99532067; COSMIC: COSV99532067;