rs147648476

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_138773.4(SLC25A46):c.148C>A(p.Pro50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,580,704 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 3 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 6.52

Publications

2 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
pontocerebellar hypoplasia, type 1E
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
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

new If you want to explore the variant's impact on the transcript NM_138773.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000525 (80/152350) while in subpopulation AMR AF = 0.00157 (24/15310). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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	UniProt
SLC25A46	NM_138773.4	MANE Select	c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3		c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3		c.10+1020C>A		intron	N/A	NP_001290179.1	B4DY98

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
SLC25A46	ENST00000923605.1		c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000593664.1
SLC25A46	ENST00000447245.6	TSL:2	c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000256

AC:

AN:

191398

AF XY:

0.000242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000678

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000457

Gnomad OTH exome

AF:

0.000604

GnomAD4 exome

AF:

0.000551

AC:

787

AN:

1428354

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

358

AN XY:

707296

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

33014

American (AMR)

AF:

0.000432

AC:

AN:

39356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25448

East Asian (EAS)

AF:

0.00

AC:

AN:

38222

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81634

European-Finnish (FIN)

AF:

0.0000401

AC:

AN:

49830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000656

AC:

719

AN:

1095972

Other (OTH)

AF:

0.000778

AC:

AN:

59144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000525

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41586

American (AMR)

AF:

0.00157

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000747

Hom.:

Bravo

AF:

0.000737

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

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

not specified (1)

Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.46

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.4

PhyloP100

6.5

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.67

gMVP

0.68

Mutation Taster

=14/86

disease causing

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over