NM_138773.4:c.938_940dupATT

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_138773.4(SLC25A46):c.938_940dupATT(p.Tyr313dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,694 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

SLC25A46
NM_138773.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:3

Conservation

PhyloP100: 0.266

Publications

1 publications found

Variant links:

Genes affected

SLC25A46 (HGNC:25198): (solute carrier family 25 member 46) This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]

SLC25A46 Gene-Disease associations (from GenCC):

neuropathy, hereditary motor and sensory, type 6B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
pontocerebellar hypoplasia, type 1E
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary motor and sensory neuropathy type 6
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC25A46 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_138773.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 5-110761460-C-CTTA is Benign according to our data. Variant chr5-110761460-C-CTTA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542458.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000979 (149/152142) while in subpopulation NFE AF = 0.00185 (126/67970). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4 link	c.938_940dupATT	p.Tyr313dup	disruptive_inframe_insertion	Exon 8 of 8	ENST00000355943.8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3 link	c.695_697dupATT	p.Tyr232dup	disruptive_inframe_insertion	Exon 8 of 8		NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3 link	c.665_667dupATT	p.Tyr222dup	disruptive_inframe_insertion	Exon 8 of 8		NP_001290179.1	Q96AG3B4DY98
SLC25A46	NR_138151.2 link	n.1177_1179dupATT		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8 link	c.938_940dupATT	p.Tyr313dup	disruptive_inframe_insertion	Exon 8 of 8	1	NM_138773.4	ENSP00000348211.3		Q96AG3-1

Frequencies

GnomAD3 genomes

AF:

0.000980

AC:

149

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00122

AC:

305

AN:

250482

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000649

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00143

AC:

2085

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

1032

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33460

American (AMR)

AF:

0.000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00174

AC:

1939

AN:

1111820

Other (OTH)

AF:

0.00108

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

135

270

406

541

676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000979

AC:

149

AN:

152142

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41548

American (AMR)

AF:

0.000131

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00185

AC:

126

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00132

Hom.:

Bravo

AF:

0.000926

EpiCase

AF:

0.00147

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jun 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in an individual with late onset spinocerebellar ataxia in whom a second SLC25A46 variant was not identified (PMID: 34445196); Identified in an individual with hereditary motor neuropathy in whom a second SLC25A46 variant was not identified (PMID: 31847883); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In-frame insertion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 36920900, 34445196, 31847883) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC25A46: PM4:Supporting -

Spastic ataxia

Pathogenic:1

Jul 12, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC25A46-related disorder

Benign:1

Feb 02, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Inborn genetic diseases

Benign:1

Dec 28, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

Mutation Taster

=47/53

disease causing

(source)

Splicing

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