rs121912444

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000454.5(SOD1):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOD1
NM_000454.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.53

Variant links:

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 links:

SOD1-DT (HGNC:55683): (SOD1 divergent transcript)

SOD1-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 7) in uniprot entity SODC_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000454.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-31659782-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 21-31659782-G-A is Pathogenic according to our data. Variant chr21-31659782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 5	ENST00000270142.11	NP_000445.1
SOD1-DT	NR_187558.1 link	n.243C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOD1	ENST00000270142.11 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 5	1	NM_000454.5	ENSP00000270142.7	P00441
SOD1	ENST00000389995.4 link	c.13G>A	p.Ala5Thr	missense_variant, splice_region_variant	Exon 1 of 5	3		ENSP00000374645.4	H7BYH4
SOD1	ENST00000470944.1 link	n.74G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2
SOD1	ENST00000476106.5 link	n.90G>A		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250486

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727088

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1

Pathogenic:3

Jun 11, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the SOD1 protein (p.Ala5Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8179602, 12792143, 17543992, 22292843). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ala4Thr. ClinVar contains an entry for this variant (Variation ID: 14765). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 8179602, 17543992, 21257910, 23280792, 26362407). This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8351519, 19176896, 19618436). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Mar 09, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;T

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.1

D;N

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;T

Sift4G

Pathogenic

0.0010

D;T

Polyphen

0.99

D;.

Vest4

0.62

MutPred

0.96

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.98

MPC

2.3

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over