rs141213807

Positions:

chr5-110761292-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_138773.4(SLC25A46):c.767A>G(p.Lys256Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00241 in 1,613,730 control chromosomes in the GnomAD database, including 15 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 13 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.89

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_138773.4

BP4

Computational evidence support a benign effect (MetaRNN=0.012173474).

BP6

Variant 5-110761292-A-G is Benign according to our data. Variant chr5-110761292-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 475800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110761292-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00187 (284/152160) while in subpopulation NFE AF= 0.00285 (194/67976). AF 95% confidence interval is 0.00252. There are 2 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A46	NM_138773.4 linkuse as main transcript	c.767A>G	p.Lys256Arg	missense_variant	8/8	ENST00000355943.8
SLC25A46	NM_001303250.3 linkuse as main transcript	c.494A>G	p.Lys165Arg	missense_variant	8/8
SLC25A46	NM_001303249.3 linkuse as main transcript	c.679-155A>G		intron_variant
SLC25A46	NR_138151.2 linkuse as main transcript	n.1006A>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8 linkuse as main transcript	c.767A>G	p.Lys256Arg	missense_variant	8/8	1	NM_138773.4	P1	Q96AG3-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00216

AC:

543

AN:

250884

Hom.:

AF XY:

0.00234

AC XY:

317

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00247

AC:

3609

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

1778

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00108

Gnomad4 FIN exome

AF:

0.00234

Gnomad4 NFE exome

AF:

0.00274

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00187

AC:

284

AN:

152160

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00217

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00196

AC:

238

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00468

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2020	This variant is associated with the following publications: (PMID: 32259769) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SLC25A46: BS2 -

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

SLC25A46-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2022

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

Mar 19, 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

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0062

T;T;.;T

Eigen

Benign

0.021

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.6

.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.40

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.76

T;T;T;T

Sift4G

Benign

0.78

T;T;T;T

Polyphen

0.0080

.;B;.;.

Vest4

0.21

MVP

0.56

MPC

0.16

ClinPred

0.017

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.49

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

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