5-110739315-G-T

Variant summary

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

The NM_138773.4(SLC25A46):c.196G>T(p.Val66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,416,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. V66V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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=0.13900882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.196G>T	p.Val66Leu	missense_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.196G>T	p.Val66Leu	missense_variant	1/8
SLC25A46	NM_001303250.3	c.10+1068G>T		intron_variant
SLC25A46	NR_138151.2	n.309G>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.196G>T	p.Val66Leu	missense_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.196G>T	p.Val66Leu	missense_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+1068G>T		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+1068G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000706 AC: 10 AN: 1416874 Hom.: 0 Cov.: 31 AF XY: 0.00000999 AC XY: 7 AN XY: 700704

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: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000826

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Invitae

Jun 20, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 475792). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 66 of the SLC25A46 protein (p.Val66Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.0076	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.19
Sift	Benign	0.27	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0060	B;.
Vest4		0.075
MutPred		0.066		Gain of glycosylation at P63 (P = 0.1607);Gain of glycosylation at P63 (P = 0.1607);
MVP		0.67
MPC		0.057
ClinPred		0.64	D
GERP RS		3.2
Varity_R		0.11
gMVP		0.29

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: rs758140632; hg19: chr5-110075016;