5-110761659-G-C

Variant names:

• chr5-110761659-G-C
• rs1164068029
• NM_138773.4:c.1134G>C

Variant summary

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

The NM_138773.4(SLC25A46):​c.1134G>C​(p.Gln378His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,432 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0670

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=0.18003255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.1134G>C	p.Gln378His	missense_variant	Exon 8 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3	c.891G>C	p.Gln297His	missense_variant	Exon 8 of 8		NP_001290178.1
SLC25A46	NM_001303250.3	c.861G>C	p.Gln287His	missense_variant	Exon 8 of 8		NP_001290179.1
SLC25A46	NR_138151.2	n.1373G>C		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.1134G>C	p.Gln378His	missense_variant	Exon 8 of 8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250938 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461432 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727008

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Dec 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with histidine at codon 378 of the SLC25A46 protein (p.Gln378His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC25A46-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.;.;T
Eigen	Benign	0.099
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;T;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.3	.;L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.071	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.91	.;P;.;.;.
Vest4		0.32
MutPred		0.31		.;Gain of methylation at R377 (P = 0.081);.;.;.;
MVP		0.70
MPC		0.22
ClinPred		0.58	D
GERP RS		2.8
Varity_R		0.064
gMVP		0.71

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: rs1164068029; hg19: chr5-110097359;