5-110738249-T-C

Position:

• chr5-110738249-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001303250.3(SLC25A46):​c.10+2T>C variant causes a splice donor 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
• Scores: Splicing: ADA: 0.5943
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 1.39

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]

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_001303250.3	c.10+2T>C		splice_donor_variant
TMEM232	XM_006714670.4	c.-298+473A>G		intron_variant
TMEM232	XM_011543552.3	c.-649+473A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000513807.5	c.-204+2T>C		splice_donor_variant		2
TMEM232	ENST00000515278.6	c.-298+473A>G		intron_variant		5
TMEM232	ENST00000503527.6	n.197+473A>G		intron_variant, non_coding_transcript_variant		3
SLC25A46	ENST00000508781.5	n.112+2T>C		splice_donor_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000540 AC: 82 AN: 151928 Hom.: 0 Cov.: 32

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: 51 AN: 126476 Hom.: 0 AF XY: 0.000346 AC XY: 24 AN XY: 69308

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.: 1 Cov.: 29 AF XY: 0.000927 AC XY: 516 AN XY: 556450

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: 82 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74322

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.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
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

Other links and lift over

dbSNP: rs147877745; hg19: chr5-110073950;