Genetic Variant SOD1:c.-83T>C (chr21-31659687-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000389995.4(SOD1):c.-83T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,433,550 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00053 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 6 hom. )

Consequence

SOD1
ENST00000389995.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.41

Publications

1 publications found

Variant links:

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 links:

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

SOD1-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 21-31659687-T-C is Benign according to our data. Variant chr21-31659687-T-C is described in ClinVar as Benign. ClinVar VariationId is 339662.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000525 (80/152348) while in subpopulation EAS AF = 0.0132 (68/5170). AF 95% confidence interval is 0.0106. There are 2 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000389995.4. 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-DT	NR_187558.1		n.338A>G		non_coding_transcript_exon	Exon 1 of 3
	SOD1	NM_000454.5	MANE Select	c.-83T>C		upstream_gene	N/A	NP_000445.1	P00441

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
SOD1	ENST00000877328.1	c.-83T>C	5_prime_UTR	Exon 1 of 4	ENSP00000547387.1
SOD1	ENST00000928717.1	c.-83T>C	5_prime_UTR	Exon 1 of 5	ENSP00000598776.1
SOD1	ENST00000928718.1	c.-83T>C	5_prime_UTR	Exon 1 of 5	ENSP00000598777.1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000377

AC:

483

AN:

1281202

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

237

AN XY:

645702

show subpopulations

African (AFR)

AF:

0.000133

AC:

AN:

29986

American (AMR)

AF:

0.00

AC:

AN:

43878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24866

East Asian (EAS)

AF:

0.0105

AC:

405

AN:

38680

South Asian (SAS)

AF:

0.000267

AC:

AN:

82454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.00000105

AC:

AN:

950510

Other (OTH)

AF:

0.000937

AC:

AN:

54450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000525

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0132

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000725

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic lateral sclerosis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.1

(source)

DANN

Benign

0.43

PhyloP100

-2.4

PromoterAI

-0.0069

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over