chr21-31659661-A-G

Variant names:

• chr21-31659661-A-G
• rs7277748
• NR_187558.1:n.364T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NR_187558.1(SOD1-DT):​n.364T>C variant causes a non coding transcript exon 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-DT NR_187558.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.586
• Publications: 15 publications found

Genes affected

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

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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic tetraplegia and axial hypotonia, progressive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 339660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_187558.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1-DT	NR_187558.1		n.364T>C		non_coding_transcript_exon	Exon 1 of 3
	SOD1	NM_000454.5	MANE Select	c.-109A>G		upstream_gene	N/A	NP_000445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.-109A>G		upstream_gene	N/A	ENSP00000270142.7
	SOD1	ENST00000389995.4	TSL:3	c.-109A>G		upstream_gene	N/A	ENSP00000374645.4
	SOD1-DT	ENST00000449339.1	TSL:3	n.-161T>C		upstream_gene	N/A

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

African (AFR) AF: 0.137 AC: 3421 AN: 24962

American (AMR) AF: 0.00813 AC: 324 AN: 39846

Ashkenazi Jewish (ASJ) AF: 0.000567 AC: 13 AN: 22916

East Asian (EAS) AF: 0.00 AC: 0 AN: 36020

South Asian (SAS) AF: 0.000200 AC: 15 AN: 75028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44840

Middle Eastern (MID) AF: 0.00683 AC: 34 AN: 4980

European-Non Finnish (NFE) AF: 0.000383 AC: 282 AN: 736510

Other (OTH) AF: 0.00984 AC: 456 AN: 46348

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

African (AFR) AF: 0.130 AC: 5387 AN: 41548

American (AMR) AF: 0.0154 AC: 235 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68026

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0273 Hom.: 136

Bravo AF: 0.0428

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17636481)

Amyotrophic lateral sclerosis type 1 Benign:2

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.71
PhyloP100		0.59
PromoterAI		-0.63	Under-expression
Mutation Taster		=292/8	polymorphism (auto)

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