rs200566665

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138773.4(SLC25A46):c.235G>A(p.Glu79Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00198 in 1,561,996 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E79Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 9 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 5.64

Publications

3 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008162528).

BP6

Variant 5-110739354-G-A is Benign according to our data. Variant chr5-110739354-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542455.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00141 (214/152034) while in subpopulation NFE AF = 0.00256 (174/67940). AF 95% confidence interval is 0.00225. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC25A46	NM_138773.4 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 1 of 8		NP_001290178.1
SLC25A46	NR_138151.2 link	n.348G>A		non_coding_transcript_exon_variant	Exon 1 of 9
SLC25A46	NM_001303250.3 link	c.10+1107G>A		intron_variant	Intron 1 of 7		NP_001290179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC25A46	ENST00000355943.8 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3
SLC25A46	ENST00000447245.6 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 1 of 8	2		ENSP00000399717.2
SLC25A46	ENST00000513807.5 link	c.-204+1107G>A		intron_variant	Intron 1 of 7	2		ENSP00000421134.1
SLC25A46	ENST00000508781.5 link	n.112+1107G>A		intron_variant	Intron 1 of 7	4

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00136

AC:

227

AN:

167026

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.000533

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000241

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.00204

AC:

2881

AN:

1409962

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1421

AN XY:

697136

show subpopulations

African (AFR)

AF:

0.000492

AC:

AN:

32536

American (AMR)

AF:

0.000561

AC:

AN:

37450

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37300

South Asian (SAS)

AF:

0.000323

AC:

AN:

80492

European-Finnish (FIN)

AF:

0.000265

AC:

AN:

45352

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00244

AC:

2649

AN:

1087218

Other (OTH)

AF:

0.00157

AC:

AN:

58612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

207

415

622

830

1037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00141

AC:

214

AN:

152034

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000434

AC:

AN:

41498

American (AMR)

AF:

0.000719

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

67940

Other (OTH)

AF:

0.00190

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.00202

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000460

AC:

ESP6500EA

AF:

0.00200

AC:

ExAC

AF:

0.00122

AC:

144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jun 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in the peer-reviewed literature to our knowledge; This variant is associated with the following publications: (PMID: Liu_2022[Preprint]) -

Feb 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC25A46: BS2 -

not specified

Benign:1

May 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC25A46 c.235G>A (p.Glu79Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0014 in 167026 control chromosomes, predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC25A46 causing Neuropathy, hereditary motor and sensory, type 6B phenotype (0.0011). To our knowledge, no occurrence of c.235G>A in individuals affected with Neuropathy, hereditary motor and sensory, type 6B and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 542455). Based on the evidence outlined above, the variant was classified as likely benign. -

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 15, 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

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0081

T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.7

L;L

PhyloP100

5.6

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.22

Sift

Benign

0.12

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;.

Vest4

0.44

MVP

0.67

MPC

0.065

ClinPred

0.054

GERP RS

3.1

PromoterAI

0.0026

Neutral

(source)

Varity_R

0.14

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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