rs16988404

Variant names:

• chr21-31663682-T-A
• rs16988404
• NM_000454.5:c.73-108T>A

Your query was ambiguous. Multiple possible variants found:

• chr21-31663682-T-A
• chr21-31663682-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000454.5(SOD1):​c.73-108T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 859,572 control chromosomes in the GnomAD database, including 846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (128 hom., cov: 32)
  • Exomes 𝑓: 0.039 (718 hom.)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.159
• Publications: 2 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-31663682-T-A is Benign according to our data. Variant chr21-31663682-T-A is described in ClinVar as Benign. ClinVar VariationId is 440292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0334 (5090/152250) while in subpopulation NFE AF = 0.0474 (3223/68002). AF 95% confidence interval is 0.046. There are 128 homozygotes in GnomAd4. There are 2533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 128 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.73-108T>A		intron	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.73-108T>A		intron	N/A	ENSP00000270142.7
	SOD1	ENST00000389995.4	TSL:3	c.16-108T>A		intron	N/A	ENSP00000374645.4
	SOD1	ENST00000470944.1	TSL:2	n.1001-108T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5088 AN: 152132 Hom.: 128 Cov.: 32

Gnomad AFR AF: 0.00821

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0388 AC: 27465 AN: 707322 Hom.: 718 AF XY: 0.0375 AC XY: 14094 AN XY: 375638

African (AFR) AF: 0.00649 AC: 122 AN: 18804

American (AMR) AF: 0.0182 AC: 674 AN: 37022

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 394 AN: 19096

East Asian (EAS) AF: 0.000253 AC: 8 AN: 31610

South Asian (SAS) AF: 0.00996 AC: 680 AN: 68248

European-Finnish (FIN) AF: 0.0875 AC: 3991 AN: 45622

Middle Eastern (MID) AF: 0.0188 AC: 58 AN: 3082

European-Non Finnish (NFE) AF: 0.0453 AC: 20387 AN: 450532

Other (OTH) AF: 0.0346 AC: 1151 AN: 33306

GnomAD4 genome AF: 0.0334 AC: 5090 AN: 152250 Hom.: 128 Cov.: 32 AF XY: 0.0340 AC XY: 2533 AN XY: 74456

African (AFR) AF: 0.00818 AC: 340 AN: 41550

American (AMR) AF: 0.0203 AC: 311 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5180

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4828

European-Finnish (FIN) AF: 0.0939 AC: 996 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0474 AC: 3223 AN: 68002

Other (OTH) AF: 0.0270 AC: 57 AN: 2108

Alfa AF: 0.0174 Hom.: 8

Bravo AF: 0.0271

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16036425, 9462467, 9786240)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amyotrophic lateral sclerosis type 1 Benign:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.75
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs16988404; hg19: chr21-33035995;