chr5-110761328-C-A

Variant names:

• chr5-110761328-C-A
• rs751900293
• NM_138773.4:c.803C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_138773.4(SLC25A46):​c.803C>A​(p.Thr268Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T268M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• pontocerebellar hypoplasia, type 1E

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-110761328-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422421.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.803C>A	p.Thr268Lys	missense_variant	Exon 8 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303250.3	c.530C>A	p.Thr177Lys	missense_variant	Exon 8 of 8		NP_001290179.1
SLC25A46	NR_138151.2	n.1042C>A		non_coding_transcript_exon_variant	Exon 9 of 9
SLC25A46	NM_001303249.3	c.679-119C>A		intron_variant	Intron 7 of 7		NP_001290178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.803C>A	p.Thr268Lys	missense_variant	Exon 8 of 8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 19, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T268K variant (also known as c.803C>A), located in coding exon 8 of the SLC25A46 gene, results from a C to A substitution at nucleotide position 803. The threonine at codon 268 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	.;M;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.87
MutPred		0.63		.;Gain of methylation at T268 (P = 0.014);.;.;
MVP		0.83
MPC		0.39
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.93
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs751900293; hg19: chr5-110097028;