rs1554092069

Positions:

• chr5-110746311-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138773.4(SLC25A46):​c.427G>A​(p.Val143Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V143V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09882966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.427G>A	p.Val143Ile	missense_variant	4/8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3	c.427G>A	p.Val143Ile	missense_variant	4/8		NP_001290178.1
SLC25A46	NM_001303250.3	c.154G>A	p.Val52Ile	missense_variant	4/8		NP_001290179.1
SLC25A46	NR_138151.2	n.540G>A		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.427G>A	p.Val143Ile	missense_variant	4/8	1	NM_138773.4	ENSP00000348211	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SLC25A46-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 143 of the SLC25A46 protein (p.Val143Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0083	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.13	N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.32	N;N
REVEL	Benign	0.22
Sift	Benign	0.37	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;.
Vest4		0.25
MutPred		0.34		Loss of catalytic residue at V143 (P = 0.0019);Loss of catalytic residue at V143 (P = 0.0019);
MVP		0.31
MPC		0.049
ClinPred		0.25	T
GERP RS		2.9
Varity_R		0.017
gMVP		0.33

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: rs1554092069; hg19: chr5-110082012;