5-110739162-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138773.4(SLC25A46):c.47del(p.Gly16ValfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC25A46 NM_138773.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-110739162-CG-C is Pathogenic according to our data. Variant chr5-110739162-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 655776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.47del	p.Gly16ValfsTer28	frameshift_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.47del	p.Gly16ValfsTer28	frameshift_variant	1/8
SLC25A46	NM_001303250.3	c.10+919del		intron_variant
SLC25A46	NR_138151.2	n.160del		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.47del	p.Gly16ValfsTer28	frameshift_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.47del	p.Gly16ValfsTer28	frameshift_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+919del		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+919del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397714 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689464

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 26, 2018

This sequence change creates a premature translational stop signal (p.Gly16Valfs*28) in the SLC25A46 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC25A46-related disease. Loss-of-function variants in SLC25A46 are known to be pathogenic (PMID: 26168012, 26951855, 27543974). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1580849841; hg19: chr5-110074863;