rs1057518749

Positions:

• chr5-110761404-G-GACTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138773.4(SLC25A46):​c.882_885dupTTAC​(p.Asn296fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.16

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.295 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-110761404-G-GACTT is Pathogenic according to our data. Variant chr5-110761404-G-GACTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372240.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.882_885dupTTAC	p.Asn296fs	frameshift_variant	8/8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303250.3	c.609_612dupTTAC	p.Asn205fs	frameshift_variant	8/8		NP_001290179.1
SLC25A46	NM_001303249.3	c.679-40_679-37dupTTAC		intron_variant			NP_001290178.1
SLC25A46	NR_138151.2	n.1121_1124dupTTAC		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.882_885dupTTAC	p.Asn296fs	frameshift_variant	8/8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pontocerebellar hypoplasia, type 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 06, 2021

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2022

Frameshift variant predicted to result in protein truncation, as the last 123 amino acids are replaced with 2 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26168012) -

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: rs1057518749; hg19: chr5-110097104;