21-31659722-T-A

Variant names:

• chr21-31659722-T-A
• rs142752986
• NM_000454.5:c.-48T>A

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.-48T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,593,380 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (13 hom.)
• Consequence: SOD1 NM_000454.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.00
• Publications: 0 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-DT (HGNC:55683): (SOD1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 21-31659722-T-A is Benign according to our data. Variant chr21-31659722-T-A is described in ClinVar as Benign. ClinVar VariationId is 339666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (800/152352) while in subpopulation AFR AF = 0.0182 (757/41588). AF 95% confidence interval is 0.0171. There are 11 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.-48T>A		5_prime_UTR	Exon 1 of 5	NP_000445.1	P00441
	SOD1-DT	NR_187558.1		n.303A>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.-48T>A		5_prime_UTR	Exon 1 of 5	ENSP00000270142.7	P00441
	SOD1	ENST00000877332.1		c.-48T>A		5_prime_UTR	Exon 1 of 5	ENSP00000547391.1
	SOD1	ENST00000877328.1		c.-48T>A		5_prime_UTR	Exon 1 of 4	ENSP00000547387.1

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 798 AN: 152234 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00150 AC: 374 AN: 249208 AF XY: 0.00115

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000586 AC: 844 AN: 1441028 Hom.: 13 Cov.: 27 AF XY: 0.000536 AC XY: 385 AN XY: 718126

African (AFR) AF: 0.0203 AC: 670 AN: 33062

American (AMR) AF: 0.00114 AC: 51 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5724

European-Non Finnish (NFE) AF: 0.0000348 AC: 38 AN: 1093456

Other (OTH) AF: 0.00124 AC: 74 AN: 59694

GnomAD4 genome AF: 0.00525 AC: 800 AN: 152352 Hom.: 11 Cov.: 33 AF XY: 0.00511 AC XY: 381 AN XY: 74500

African (AFR) AF: 0.0182 AC: 757 AN: 41588

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.00642

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.063
DANN	Benign	0.49
PhyloP100		-3.0
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142752986; hg19: chr21-33032035;