Genetic Variant SLC25A46:p.Ile49Ile (chr5-110739266-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_138773.4(SLC25A46):c.147C>T(p.Ile49Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,580,486 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I49I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 43 hom., cov: 33)

Exomes 𝑓: 0.018 ( 287 hom. )

Consequence

SLC25A46
NM_138773.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.62

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 Gene-Disease associations (from GenCC):

neuropathy, hereditary motor and sensory, type 6B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
pontocerebellar hypoplasia, type 1E
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 5-110739266-C-T is Benign according to our data. Variant chr5-110739266-C-T is described in ClinVar as Benign. ClinVar VariationId is 475791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.62 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0231 (3518/152348) while in subpopulation AFR AF = 0.0284 (1181/41594). AF 95% confidence interval is 0.027. There are 43 homozygotes in GnomAd4. There are 1714 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 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.147C>T	p.Ile49Ile	synonymous	Exon 1 of 8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3		c.147C>T	p.Ile49Ile	synonymous	Exon 1 of 8	NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3		c.10+1019C>T		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.147C>T	p.Ile49Ile	synonymous	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
SLC25A46	ENST00000923605.1		c.147C>T	p.Ile49Ile	synonymous	Exon 1 of 8	ENSP00000593664.1
SLC25A46	ENST00000447245.6	TSL:2	c.147C>T	p.Ile49Ile	synonymous	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3518

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00945

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0339

GnomAD2 exomes

AF:

0.0190

AC:

3625

AN:

190938

AF XY:

0.0186

show subpopulations

Gnomad AFR exome

AF:

0.0257

Gnomad AMR exome

AF:

0.0192

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.0344

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0180

AC:

25738

AN:

1428138

Hom.:

287

Cov.:

AF XY:

0.0178

AC XY:

12553

AN XY:

707176

show subpopulations

African (AFR)

AF:

0.0253

AC:

835

AN:

33012

American (AMR)

AF:

0.0197

AC:

775

AN:

39300

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

271

AN:

25444

East Asian (EAS)

AF:

0.00759

AC:

290

AN:

38218

South Asian (SAS)

AF:

0.00824

AC:

673

AN:

81642

European-Finnish (FIN)

AF:

0.0316

AC:

1575

AN:

49780

Middle Eastern (MID)

AF:

0.0162

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0183

AC:

20073

AN:

1095874

Other (OTH)

AF:

0.0195

AC:

1153

AN:

59134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1694

3388

5081

6775

8469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.0231

AC:

3518

AN:

152348

Hom.:

Cov.:

AF XY:

0.0230

AC XY:

1714

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0284

AC:

1181

AN:

41594

American (AMR)

AF:

0.0248

AC:

379

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.00947

AC:

AN:

5172

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0357

AC:

379

AN:

10630

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0199

AC:

1355

AN:

68026

Other (OTH)

AF:

0.0336

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0161

Hom.:

Bravo

AF:

0.0219

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.6

PromoterAI

0.055

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(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

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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