5-110739253-C-T

Variant names:

• chr5-110739253-C-T
• rs1554091122
• NM_138773.4:c.134C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_138773.4(SLC25A46):​c.134C>T​(p.Thr45Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,431,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity S2546_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29353255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.134C>T	p.Thr45Ile	missense_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3	c.134C>T	p.Thr45Ile	missense_variant	Exon 1 of 8		NP_001290178.1
SLC25A46	NM_001303250.3	c.10+1006C>T		intron_variant	Intron 1 of 7		NP_001290179.1
SLC25A46	NR_138151.2	n.247C>T		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.134C>T	p.Thr45Ile	missense_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3
SLC25A46	ENST00000447245.6	c.134C>T	p.Thr45Ile	missense_variant	Exon 1 of 8	2		ENSP00000399717.2
SLC25A46	ENST00000513807.5	c.-204+1006C>T		intron_variant	Intron 1 of 7	2		ENSP00000421134.1
SLC25A46	ENST00000508781.5	n.112+1006C>T		intron_variant	Intron 1 of 7	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1431694 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709284

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: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on SLC25A46 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces threonine with isoleucine at codon 45 of the SLC25A46 protein (p.Thr45Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an SLC25A46-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.0085
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.015	B;.
Vest4		0.29
MutPred		0.30		Loss of glycosylation at T45 (P = 0.0204);Loss of glycosylation at T45 (P = 0.0204);
MVP		0.74
MPC		0.098
ClinPred		0.94	D
GERP RS		3.3
Varity_R		0.28
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554091122; hg19: chr5-110074954;