rs80265967

Variant names:

• chr21-31667290-A-C
• rs80265967
• NM_000454.5:c.272A>C

Your query was ambiguous. Multiple possible variants found:

• chr21-31667290-A-C
• chr21-31667290-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PS3 PM1 PM5 PP2 BP4_Moderate

The NM_000454.5(SOD1):​c.272A>C​(p.Asp91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,614,112 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005040188: Several publications report experimental evidence evaluating an impact on protein function (e.g. Anderson_1995, Lindberg_2002, Jonsson_2002, Prudencio_2009, Chen_2023). While the variant does not appear to negatively affect Cu-Zn-SOD activity, in at least two studies it has been found to result in significantly increased protein aggregation compared to the wild type protein (e.g. Prudencio_2009, Chen_2023). PMID:9817920, 7647793, 34996976, 36376198, 20460594, 12270693, 10809943, 12482932, 19483195, 8909456" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (3 hom.)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:5 B:1
• Conservation: PhyloP100: 0.308
• Publications: 421 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: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• spastic tetraplegia and axial hypotonia, progressive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273271 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005040188: Several publications report experimental evidence evaluating an impact on protein function (e.g. Anderson_1995, Lindberg_2002, Jonsson_2002, Prudencio_2009, Chen_2023). While the variant does not appear to negatively affect Cu-Zn-SOD activity, in at least two studies it has been found to result in significantly increased protein aggregation compared to the wild type protein (e.g. Prudencio_2009, Chen_2023). PMID: 9817920, 7647793, 34996976, 36376198, 20460594, 12270693, 10809943, 12482932, 19483195, 8909456; SCV000844000: Experiments show this variant causes increased protein aggregation causing motor neuron degeneration (PMID 17146286, 18319614, 19483195, 25806427).
• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000454.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-31667290-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1802147.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 spastic tetraplegia and axial hypotonia, progressive, amyotrophic lateral sclerosis type 1, amyotrophic lateral sclerosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17195162).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.272A>C	p.Asp91Ala	missense	Exon 4 of 5	NP_000445.1	P00441

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.272A>C	p.Asp91Ala	missense	Exon 4 of 5	ENSP00000270142.7	P00441
	SOD1	ENST00000877332.1		c.410A>C	p.Asp137Ala	missense	Exon 4 of 5	ENSP00000547391.1
	SOD1	ENST00000877328.1		c.335A>C	p.Asp112Ala	missense	Exon 3 of 4	ENSP00000547387.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00143 AC: 360 AN: 251472 AF XY: 0.00134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000928 AC: 1357 AN: 1461822 Hom.: 3 Cov.: 30 AF XY: 0.000914 AC XY: 665 AN XY: 727214

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86254

European-Finnish (FIN) AF: 0.0108 AC: 579 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000616 AC: 685 AN: 1111956

Other (OTH) AF: 0.000563 AC: 34 AN: 60394

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74468

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000479 Hom.: 1

Bravo AF: 0.000302

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00112 AC: 136

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	2	-	Amyotrophic lateral sclerosis type 1 (12)
3	3	-	not provided (6)
2	-	-	Amyotrophic lateral sclerosis (2)
1	-	-	Adult onset neurodegenerative disorder (1)
1	-	-	Amyotrophic lateral sclerosis 1, autosomal recessive (1)
-	-	1	not specified (1)
1	-	-	SOD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.10	T
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.64
MVP		0.89
MPC		1.4
ClinPred		0.044	T
GERP RS		-5.9
Varity_R		0.60
gMVP		0.91
Mutation Taster		=57/43	disease causing (ClinVar)

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: rs80265967; hg19: chr21-33039603;