5-110761662-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138773.4(SLC25A46):c.1137G>T(p.Glu379Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,613,480 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E379Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 264 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 244 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028838515).

BP6

Variant 5-110761662-G-T is Benign according to our data. Variant chr5-110761662-G-T is described in ClinVar as Benign. ClinVar VariationId is 475788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4 link	c.1137G>T	p.Glu379Asp	missense_variant	Exon 8 of 8	ENST00000355943.8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3 link	c.894G>T	p.Glu298Asp	missense_variant	Exon 8 of 8		NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3 link	c.864G>T	p.Glu288Asp	missense_variant	Exon 8 of 8		NP_001290179.1	Q96AG3B4DY98
SLC25A46	NR_138151.2 link	n.1376G>T		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.1137G>T	p.Glu379Asp	missense_variant	Exon 8 of 8	1	NM_138773.4	ENSP00000348211.3		Q96AG3-1

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4955

AN:

151956

Hom.:

264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00837

AC:

2100

AN:

250924

AF XY:

0.00622

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.00565

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00524

GnomAD4 exome

AF:

0.00325

AC:

4753

AN:

1461406

Hom.:

244

Cov.:

AF XY:

0.00284

AC XY:

2067

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.114

AC:

3819

AN:

33458

American (AMR)

AF:

0.00622

AC:

278

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00199

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000174

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000873

AC:

AN:

1111706

Other (OTH)

AF:

0.00772

AC:

466

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

265

529

794

1058

1323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.0327

AC:

4973

AN:

152074

Hom.:

264

Cov.:

AF XY:

0.0319

AC XY:

2372

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.114

AC:

4717

AN:

41488

American (AMR)

AF:

0.0121

AC:

184

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67980

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

225

450

674

899

1124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0102

Hom.:

264

Bravo

AF:

0.0380

ESP6500AA

AF:

0.112

AC:

493

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00983

AC:

1193

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.;.;T

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

D;D;T;D;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.8

.;L;.;.;.

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.029

D;T;T;D;D

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.99

.;D;.;.;.

Vest4

0.43

MutPred

0.41

.;Loss of methylation at R377 (P = 0.1893);.;.;.;

MVP

0.57

MPC

0.13

ClinPred

0.035

GERP RS

-2.2

Varity_R

0.14

gMVP

0.81

Mutation Taster

=97/3

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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