5-110739129-C-CGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138773.4(SLC25A46):c.11_12insTG(p.Arg5GlyfsTer40) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000129 in 1,547,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R4R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.38

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 18 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 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-110739129-C-CGT is Pathogenic according to our data. Variant chr5-110739129-C-CGT is described in ClinVar as [Pathogenic]. Clinvar id is 422422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.11_12insTG	p.Arg5GlyfsTer40	frameshift_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.11_12insTG	p.Arg5GlyfsTer40	frameshift_variant	1/8
SLC25A46	NM_001303250.3	c.10+883_10+884insTG		intron_variant
SLC25A46	NR_138151.2	n.124_125insTG		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.11_12insTG	p.Arg5GlyfsTer40	frameshift_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.11_12insTG	p.Arg5GlyfsTer40	frameshift_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+883_-204+884insTG		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+883_112+884insTG		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395380 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688300

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 21, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 422422). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg5Glyfs*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). -

Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Sep 08, 2023

The SLC25A46 c.11_12insTG (p.Arg5GlyfsTer40) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The variant causes a frameshift by inserting two nucleotides, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant has been reported in the ClinVar database as a pathogenic variant by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

The c.11_12insTG pathogenic mutation, located in coding exon 1 of the SLC25A46 gene, results from an insertion of two nucleotides at position 11, causing a translational frameshift with a predicted alternate stop codon (p.R5Gfs*40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2016

The c.11_12insTG variant in the SLC25A46 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11_12insTG variant causes a frameshift starting with codon Arginine 5, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Arg5GlyfsX40. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11_12insTG variant was not observed in approximately 5800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.11_12insTG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064795772; hg19: chr5-110074830;