rs1057519295

Positions:

• chr5-110746297-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 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

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a repeat Solcar 1 (size 91) in uniprot entity S2546_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_138773.4
• 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 id is 374893.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.413T>G	p.Leu138Arg	missense_variant	4/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.413T>G	p.Leu138Arg	missense_variant	4/8
SLC25A46	NM_001303250.3	c.140T>G	p.Leu47Arg	missense_variant	4/8
SLC25A46	NR_138151.2	n.526T>G		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.413T>G	p.Leu138Arg	missense_variant	4/8	1	NM_138773.4	P1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.049	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.62		Gain of catalytic residue at L138 (P = 0.0377);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519295; hg19: chr5-110081998;