rs1057519295

Variant names:

• chr5-110746297-T-G
• rs1057519295
• NM_138773.4:c.413T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_138773.4(SLC25A46):​c.413T>G​(p.Leu138Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.24
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 5-110746297-T-G is Pathogenic according to our data. Variant chr5-110746297-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 374893.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	NM_138773.4	MANE Select	c.413T>G	p.Leu138Arg	missense	Exon 4 of 8	NP_620128.1
	SLC25A46	NM_001303249.3		c.413T>G	p.Leu138Arg	missense	Exon 4 of 8	NP_001290178.1
	SLC25A46	NM_001303250.3		c.140T>G	p.Leu47Arg	missense	Exon 4 of 8	NP_001290179.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.413T>G	p.Leu138Arg	missense	Exon 4 of 8	ENSP00000348211.3
	SLC25A46	ENST00000447245.6	TSL:2	c.413T>G	p.Leu138Arg	missense	Exon 4 of 8	ENSP00000399717.2
	SLC25A46	ENST00000502462.6	TSL:2	n.729T>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jan 14, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.62		Gain of catalytic residue at L138 (P = 0.0377)
MVP		0.82
MPC		0.30
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.79
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519295; hg19: chr5-110081998;