rs114859074

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000355943.8(SLC25A46):c.631G>A(p.Val211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,572,574 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 14 hom. )

Consequence

SLC25A46
ENST00000355943.8 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.62

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008442342).

BP6

Variant 5-110756712-G-A is Benign according to our data. Variant chr5-110756712-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110756712-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00201 (306/151972) while in subpopulation NFE AF= 0.00324 (220/67930). AF 95% confidence interval is 0.00289. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC25A46	NM_138773.4 linkuse as main transcript	c.631G>A	p.Val211Met	missense_variant	7/8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3 linkuse as main transcript	c.631G>A	p.Val211Met	missense_variant	7/8		NP_001290178.1
SLC25A46	NM_001303250.3 linkuse as main transcript	c.358G>A	p.Val120Met	missense_variant	7/8		NP_001290179.1
SLC25A46	NR_138151.2 linkuse as main transcript	n.870G>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8 linkuse as main transcript	c.631G>A	p.Val211Met	missense_variant	7/8	1	NM_138773.4	ENSP00000348211	P1	Q96AG3-1

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

306

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000761

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00324

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00257

AC:

566

AN:

220192

Hom.:

AF XY:

0.00260

AC XY:

312

AN XY:

119878

show subpopulations

Gnomad AFR exome

AF:

0.000471

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00633

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000960

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.00279

AC:

3963

AN:

1420602

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

1946

AN XY:

705928

show subpopulations

Gnomad4 AFR exome

AF:

0.000357

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00687

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00103

Gnomad4 FIN exome

AF:

0.00191

Gnomad4 NFE exome

AF:

0.00304

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

151972

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

149

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000761

Gnomad4 NFE

AF:

0.00324

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00396

AC:

ExAC

AF:

0.00276

AC:

335

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC25A46: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

SLC25A46-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

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

0.086

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.027

T;T;.;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.1

.;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.047

.;B;.;.

Vest4

0.40

MVP

0.53

MPC

0.059

ClinPred

0.0039

GERP RS

2.5

Varity_R

0.031

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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