NM_000454.5:c.-55C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_000454.5(SOD1):c.-55C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,571,582 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

SOD1
NM_000454.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.59

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000422 (599/1419330) while in subpopulation EAS AF = 0.00162 (64/39478). AF 95% confidence interval is 0.0013. There are 1 homozygotes in GnomAdExome4. There are 283 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
SOD1	NM_000454.5 link	c.-55C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	ENST00000270142.11	NP_000445.1
SOD1	NM_000454.5 link	c.-55C>T	5_prime_UTR_variant	Exon 1 of 5	ENST00000270142.11	NP_000445.1
SOD1-DT	NR_187558.1 link	n.310G>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 link	c.-55C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	1	NM_000454.5	ENSP00000270142.7		P00441
SOD1	ENST00000270142.11 link	c.-55C>T		5_prime_UTR_variant	Exon 1 of 5	1	NM_000454.5	ENSP00000270142.7		P00441

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000422

AC:

599

AN:

1419330

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

283

AN XY:

708694

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32616

American (AMR)

AF:

0.0000896

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00162

AC:

AN:

39478

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85374

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000479

AC:

514

AN:

1073882

Other (OTH)

AF:

0.000203

AC:

AN:

58980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000210

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000694

Hom.:

Bravo

AF:

0.000204

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.1

(source)

DANN

Benign

0.87

PhyloP100

-1.6

PromoterAI

-0.062

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

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NM_000454.5:c.-55C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over