Variant 5-110738249-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BS1_Supporting

The NM_001303250.3(SLC25A46):c.10+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,286,456 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 1 hom. )

Consequence

SLC25A46
NM_001303250.3 splice_donor, intron

Scores

Splicing: ADA: 0.5943

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: 1.39

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 made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000539 (82/152046) while in subpopulation NFE AF= 0.000794 (54/67976). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
SLC25A46	NM_001303250.3 link	c.10+2T>C	splice_donor_variant, intron_variant	NP_001290179.1	Q96AG3B4DY98
TMEM232	XM_006714670.4 link	c.-298+473A>G	intron_variant	XP_006714733.1	C9JQI7-1
TMEM232	XM_011543552.3 link	c.-649+473A>G	intron_variant	XP_011541854.1	C9JQI7-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein	UniProt
SLC25A46	ENST00000513807.5 link	c.-204+2T>C	splice_donor_variant, intron_variant	2	ENSP00000421134.1	E7EVY2
TMEM232	ENST00000515278.6 link	c.-298+473A>G	intron_variant	5	ENSP00000421614.2	D6REY3
TMEM232	ENST00000503527.6 link	n.197+473A>G	intron_variant	3
SLC25A46	ENST00000508781.5 link	n.112+2T>C	splice_donor_variant, intron_variant	4

Frequencies

GnomAD3 genomes

AF:

0.000540

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

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:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000403

AC:

AN:

126476

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

69308

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.0000421

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000892

Gnomad OTH exome

AF:

0.000256

GnomAD4 exome

AF:

0.000980

AC:

1112

AN:

1134410

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

516

AN XY:

556450

show subpopulations

Gnomad4 AFR exome

AF:

0.000989

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:

0.000318

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.000653

GnomAD4 genome

AF:

0.000539

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000651

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000323

Hom.:

Bravo

AF:

0.000570

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Pathogenic

0.76

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