Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138773.4(SLC25A46):c.52G>T(p.Ala18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,550,642 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.843

Publications

1 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 links:

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM232 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=0.0045889914).

BP6

Variant 5-110739171-G-T is Benign according to our data. Variant chr5-110739171-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 542454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0036 (548/152346) while in subpopulation AFR AF = 0.0128 (532/41582). AF 95% confidence interval is 0.0119. There are 6 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A46	NM_138773.4	MANE Select	c.52G>T	p.Ala18Ser	missense	Exon 1 of 8	NP_620128.1
SLC25A46	NM_001303249.3		c.52G>T	p.Ala18Ser	missense	Exon 1 of 8	NP_001290178.1
SLC25A46	NR_138151.2		n.165G>T		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.52G>T	p.Ala18Ser	missense	Exon 1 of 8	ENSP00000348211.3
SLC25A46	ENST00000447245.6	TSL:2	c.52G>T	p.Ala18Ser	missense	Exon 1 of 8	ENSP00000399717.2
SLC25A46	ENST00000513807.5	TSL:2	c.-204+924G>T		intron	N/A	ENSP00000421134.1

Frequencies

GnomAD3 genomes

AF:

0.00359

AC:

547

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000664

AC:

102

AN:

153694

AF XY:

0.000588

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.000445

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000367

AC:

513

AN:

1398296

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

228

AN XY:

689794

show subpopulations

African (AFR)

AF:

0.0137

AC:

434

AN:

31650

American (AMR)

AF:

0.000476

AC:

AN:

35730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35834

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48100

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.00000741

AC:

AN:

1079164

Other (OTH)

AF:

0.000845

AC:

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00360

AC:

548

AN:

152346

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0128

AC:

532

AN:

41582

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000781

Hom.:

Bravo

AF:

0.00370

ESP6500AA

AF:

0.00961

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000564

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Neuropathy, hereditary motor and sensory, type 6B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0033

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

PhyloP100

0.84

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.19

REVEL

Benign

0.18

Sift

Benign

0.38

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.059

MVP

0.55

MPC

0.052

ClinPred

0.021

GERP RS

4.0

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over