rs200566665

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

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. 12/21 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. E79D) 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:3

Conservation

PhyloP100: 5.64

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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 id is 542455.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr5-110739354-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A46	NM_138773.4 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	1/8
SLC25A46	NM_001303250.3 linkuse as main transcript	c.10+1107G>A		intron_variant
SLC25A46	NR_138151.2 linkuse as main transcript	n.348G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	1/8	1	NM_138773.4	P1	Q96AG3-1
SLC25A46	ENST00000447245.6 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	1/8	2			Q96AG3-3
SLC25A46	ENST00000513807.5 linkuse as main transcript	c.-204+1107G>A		intron_variant		2
SLC25A46	ENST00000508781.5 linkuse as main transcript	n.112+1107G>A		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes

AF:

0.00136

AC:

227

AN:

167026

Hom.:

AF XY:

0.00120

AC XY:

108

AN XY:

89762

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 SAS exome

AF:

0.000543

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

Gnomad4 AFR exome

AF:

0.000492

Gnomad4 AMR exome

AF:

0.000561

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000323

Gnomad4 FIN exome

AF:

0.000265

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152034

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00200

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:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	Observed with another variant in one individual with Parkinson disease; however, it is unknown whether these variants are on the same (in cis) or opposite (in trans) chromosomes (Liu et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Liu_2022[Preprint]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2022	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SLC25A46: BS2 -

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2019

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

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

MutationTaster

Benign

1.0

D;D;N;N

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

Varity_R

0.14

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over