rs1057519416

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_138773.4(SLC25A46):c.166dup(p.His56ProfsTer40) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000159 in 1,575,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SLC25A46
NM_138773.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.47

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-110739284-G-GC is Pathogenic according to our data. Variant chr5-110739284-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 372237.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A46	NM_138773.4 linkuse as main transcript	c.166dup	p.His56ProfsTer40	frameshift_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3 linkuse as main transcript	c.166dup	p.His56ProfsTer40	frameshift_variant	1/8
SLC25A46	NM_001303250.3 linkuse as main transcript	c.10+1038dup		intron_variant
SLC25A46	NR_138151.2 linkuse as main transcript	n.279dup		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8 linkuse as main transcript	c.166dup	p.His56ProfsTer40	frameshift_variant	1/8	1	NM_138773.4	P1	Q96AG3-1
SLC25A46	ENST00000447245.6 linkuse as main transcript	c.166dup	p.His56ProfsTer40	frameshift_variant	1/8	2			Q96AG3-3
SLC25A46	ENST00000513807.5 linkuse as main transcript	c.-204+1038dup		intron_variant		2
SLC25A46	ENST00000508781.5 linkuse as main transcript	n.112+1038dup		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181816

Hom.:

AF XY:

0.0000102

AC XY:

AN XY:

97632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1422902

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

704104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000211

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 01, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372237). This premature translational stop signal has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 26168012). This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.His56Profs*40) in the SLC25A46 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A46 are known to be pathogenic (PMID: 26168012, 26951855, 27543974). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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