rs8091858

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006796.3(AFG3L2):c.1026+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,613,348 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 61 hom., cov: 33)

Exomes 𝑓: 0.025 ( 527 hom. )

Consequence

AFG3L2
NM_006796.3 splice_region, intron

Scores

Splicing: ADA: 0.0001617

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.171

Publications

5 publications found

Variant links:

Genes affected

AFG3L2 (HGNC:315): (AFG3 like matrix AAA peptidase subunit 2) This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders. [provided by RefSeq, Jul 2008]

AFG3L2 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 28
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp
spastic ataxia 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
optic atrophy 12
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

AFG3L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 18-12358662-C-T is Benign according to our data. Variant chr18-12358662-C-T is described in ClinVar as Benign. ClinVar VariationId is 136313.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 = 0.0231 (3523/152324) while in subpopulation NFE AF = 0.0307 (2086/68020). AF 95% confidence interval is 0.0296. There are 61 homozygotes in GnomAd4. There are 1792 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 61 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG3L2	NM_006796.3 link	c.1026+8G>A		splice_region_variant, intron_variant	Intron 8 of 16	ENST00000269143.8	NP_006787.2	Q9Y4W6Q8TA92
AFG3L2	XM_011525601.4 link	c.1026+8G>A		splice_region_variant, intron_variant	Intron 8 of 15		XP_011523903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8 link	c.1026+8G>A		splice_region_variant, intron_variant	Intron 8 of 16	1	NM_006796.3	ENSP00000269143.2		Q9Y4W6

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3524

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0665

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00972

Gnomad FIN

AF:

0.0501

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0307

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0245

AC:

6104

AN:

249578

AF XY:

0.0243

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.0164

Gnomad ASJ exome

AF:

0.0618

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0500

Gnomad NFE exome

AF:

0.0297

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0250

AC:

36528

AN:

1461024

Hom.:

527

Cov.:

AF XY:

0.0249

AC XY:

18096

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.00353

AC:

118

AN:

33466

American (AMR)

AF:

0.0180

AC:

805

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0618

AC:

1613

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00822

AC:

708

AN:

86162

European-Finnish (FIN)

AF:

0.0454

AC:

2421

AN:

53354

Middle Eastern (MID)

AF:

0.0286

AC:

165

AN:

5760

European-Non Finnish (NFE)

AF:

0.0263

AC:

29227

AN:

1111462

Other (OTH)

AF:

0.0244

AC:

1471

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1782

3564

5346

7128

8910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1042

2084

3126

4168

5210

<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:

0.0231

AC:

3523

AN:

152324

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

1792

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00491

AC:

204

AN:

41582

American (AMR)

AF:

0.0212

AC:

324

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

231

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00973

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0501

AC:

532

AN:

10612

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0307

AC:

2086

AN:

68020

Other (OTH)

AF:

0.0261

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

182

364

547

729

911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0274

Hom.:

118

Bravo

AF:

0.0204

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

AFG3L2-related disorder

Benign:1

Sep 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spinocerebellar ataxia type 28

Benign:1

Jan 12, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.5

(source)

DANN

Benign

0.63

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.016

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over