21-31667716-A-G

Variant names:

• chr21-31667716-A-G
• rs4816407
• NM_000454.5:c.357+341A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000454.5(SOD1):​c.357+341A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,184 control chromosomes in the GnomAD database, including 2,910 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2910 hom., cov: 32)
• Consequence: SOD1 NM_000454.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.750
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.357+341A>G		intron_variant	Intron 4 of 4	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.357+341A>G		intron_variant	Intron 4 of 4	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000389995.4	c.300+341A>G		intron_variant	Intron 4 of 4	3		ENSP00000374645.4
SOD1	ENST00000470944.1	n.1285+341A>G		intron_variant	Intron 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23326 AN: 152066 Hom.: 2892 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0963

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.120

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.154 AC: 23382 AN: 152184 Hom.: 2910 Cov.: 32 AF XY: 0.158 AC XY: 11780 AN XY: 74412

African (AFR) AF: 0.270 AC: 11208 AN: 41472

American (AMR) AF: 0.211 AC: 3223 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3468

East Asian (EAS) AF: 0.514 AC: 2660 AN: 5174

South Asian (SAS) AF: 0.207 AC: 999 AN: 4822

European-Finnish (FIN) AF: 0.0963 AC: 1022 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0549 AC: 3736 AN: 68016

Other (OTH) AF: 0.122 AC: 258 AN: 2112

Alfa AF: 0.102 Hom.: 2175

Bravo AF: 0.171

Asia WGS AF: 0.340 AC: 1182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.11
DANN	Benign	0.70
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs4816407; hg19: chr21-33040029;