rs7277748

chr21-31659661-A-Gchr21-31659661-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The 21-31659661-A-G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,183,742 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (334 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (218 hom.)
• Consequence: SOD1 NM_000454.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.586

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 21-31659661-A-G is Benign according to our data. Variant chr21-31659661-A-G is described in ClinVar as [Benign]. Clinvar id is 339660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-31659661-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD1	NM_000454.5			upstream_gene_variant		ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11			upstream_gene_variant		1	NM_000454.5	P1
SOD1	ENST00000389995.4			upstream_gene_variant		3
SOD1	ENST00000470944.1			upstream_gene_variant		2
SOD1	ENST00000476106.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5714 AN: 152174 Hom.: 331 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.00441 AC: 4545 AN: 1031450 Hom.: 218 Cov.: 13 AF XY: 0.00385 AC XY: 2036 AN XY: 528820

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.00813

Gnomad4 ASJ exome AF: 0.000567

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.00984

GnomAD4 genome AF: 0.0377 AC: 5736 AN: 152292 Hom.: 334 Cov.: 33 AF XY: 0.0359 AC XY: 2670 AN XY: 74472

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.00769 Hom.: 27

Bravo AF: 0.0428

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2019	This variant is associated with the following publications: (PMID: 17636481) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs7277748; hg19: chr21-33031974; COSMIC: COSV54256003; COSMIC: COSV54256003;