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

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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:2

Conservation

PhyloP100: 1.62

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 -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 id is 475791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110739266-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4 link	c.147C>T	p.Ile49Ile	synonymous_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3 link	c.147C>T	p.Ile49Ile	synonymous_variant	Exon 1 of 8		NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3 link	c.10+1019C>T		intron_variant	Intron 1 of 7		NP_001290179.1	Q96AG3B4DY98
SLC25A46	NR_138151.2 link	n.260C>T		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC25A46	ENST00000355943.8 link	c.147C>T	p.Ile49Ile	synonymous_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3	Q96AG3-1
SLC25A46	ENST00000447245.6 link	c.147C>T	p.Ile49Ile	synonymous_variant	Exon 1 of 8	2		ENSP00000399717.2	Q96AG3-3
SLC25A46	ENST00000513807.5 link	c.-204+1019C>T		intron_variant	Intron 1 of 7	2		ENSP00000421134.1	E7EVY2
SLC25A46	ENST00000508781.5 link	n.112+1019C>T		intron_variant	Intron 1 of 7	4

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

GnomAD3 exomes

AF:

0.0190

AC:

3625

AN:

190938

Hom.:

AF XY:

0.0186

AC XY:

1910

AN XY:

102930

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 SAS exome

AF:

0.00805

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

Gnomad4 AFR exome

AF:

0.0253

Gnomad4 AMR exome

AF:

0.0197

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.00759

Gnomad4 SAS exome

AF:

0.00824

Gnomad4 FIN exome

AF:

0.0316

Gnomad4 NFE exome

AF:

0.0183

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0231

AC:

3518

AN:

152348

Hom.:

Cov.:

AF XY:

0.0230

AC XY:

1714

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0284

Gnomad4 AMR

AF:

0.0248

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00947

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0357

Gnomad4 NFE

AF:

0.0199

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0219

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.95

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