chr5-110739267-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_138773.4(SLC25A46):c.148C>A(p.Pro50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,580,704 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 3 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 6.52

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000525 (80/152350) while in subpopulation AMR AF = 0.00157 (24/15310). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC25A46	NM_138773.4 link	c.148C>A	p.Pro50Thr	missense_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3 link	c.148C>A	p.Pro50Thr	missense_variant	Exon 1 of 8		NP_001290178.1
SLC25A46	NR_138151.2 link	n.261C>A		non_coding_transcript_exon_variant	Exon 1 of 9
SLC25A46	NM_001303250.3 link	c.10+1020C>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.148C>A	p.Pro50Thr	missense_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3
SLC25A46	ENST00000447245.6 link	c.148C>A	p.Pro50Thr	missense_variant	Exon 1 of 8	2		ENSP00000399717.2
SLC25A46	ENST00000513807.5 link	c.-204+1020C>A		intron_variant	Intron 1 of 7	2		ENSP00000421134.1
SLC25A46	ENST00000508781.5 link	n.112+1020C>A		intron_variant	Intron 1 of 7	4

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000256

AC:

AN:

191398

AF XY:

0.000242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000678

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000457

Gnomad OTH exome

AF:

0.000604

GnomAD4 exome

AF:

0.000551

AC:

787

AN:

1428354

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

358

AN XY:

707296

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

33014

American (AMR)

AF:

0.000432

AC:

AN:

39356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25448

East Asian (EAS)

AF:

0.00

AC:

AN:

38222

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81634

European-Finnish (FIN)

AF:

0.0000401

AC:

AN:

49830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000656

AC:

719

AN:

1095972

Other (OTH)

AF:

0.000778

AC:

AN:

59144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

152350

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41586

American (AMR)

AF:

0.00157

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000747

Hom.:

Bravo

AF:

0.000737

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2025

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 to our knowledge -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neuropathy, hereditary motor and sensory, type 6B

Uncertain:1

Oct 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 50 of the SLC25A46 protein (p.Pro50Thr). This variant is present in population databases (rs147648476, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. ClinVar contains an entry for this variant (Variation ID: 542451). 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 (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Nov 29, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC25A46 c.148C>A (p.Pro50Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 191398 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A46 causing Neuropathy, hereditary motor and sensory, type 6B (0.00026 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.148C>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: 542451). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.148C>A (p.P50T) alteration is located in exon 1 (coding exon 1) of the SLC25A46 gene. This alteration results from a C to A substitution at nucleotide position 148, causing the proline (P) at amino acid position 50 to be replaced by a threonine (T). The alteration has been observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.148C>A alteration was observed in 0.03% (59/222,796) of total alleles studied, with a frequency of 0.05% (45/96,316) in the European (non-Finnish) subpopulation. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.P50T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 01-26-2022 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

6.5

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

N;N

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.99

D;.

Vest4

0.66

MVP

0.82

MPC

0.38

ClinPred

0.72

GERP RS

5.1

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.67

gMVP

0.68

Mutation Taster

=14/86

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over