5-110761662-G-T

Position:

• chr5-110761662-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000355943.8(SLC25A46):​c.1137G>T​(p.Glu379Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,613,480 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E379Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (264 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (244 hom.)
• Consequence: SLC25A46 ENST00000355943.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08

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 Benign. Variant got -18 ACMG points.

• PM1: In a repeat Solcar 2 (size 102) in uniprot entity S2546_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000355943.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028838515).
• BP6: Variant 5-110761662-G-T is Benign according to our data. Variant chr5-110761662-G-T is described in ClinVar as [Benign]. Clinvar id is 475788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110761662-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.1137G>T	p.Glu379Asp	missense_variant	8/8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3	c.894G>T	p.Glu298Asp	missense_variant	8/8		NP_001290178.1
SLC25A46	NM_001303250.3	c.864G>T	p.Glu288Asp	missense_variant	8/8		NP_001290179.1
SLC25A46	NR_138151.2	n.1376G>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.1137G>T	p.Glu379Asp	missense_variant	8/8	1	NM_138773.4	ENSP00000348211	P1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4955 AN: 151956 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00837 AC: 2100 AN: 250924 Hom.: 116 AF XY: 0.00622 AC XY: 844 AN XY: 135608

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00565

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00325 AC: 4753 AN: 1461406 Hom.: 244 Cov.: 31 AF XY: 0.00284 AC XY: 2067 AN XY: 726994

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000873

Gnomad4 OTH exome AF: 0.00772

GnomAD4 genome AF: 0.0327 AC: 4973 AN: 152074 Hom.: 264 Cov.: 32 AF XY: 0.0319 AC XY: 2372 AN XY: 74334

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00414 Hom.: 48

Bravo AF: 0.0380

ESP6500AA AF: 0.112 AC: 493

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00983 AC: 1193

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.;T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D;T;D;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.029	D;T;T;D;D
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.99	.;D;.;.;.
Vest4		0.43
MutPred		0.41		.;Loss of methylation at R377 (P = 0.1893);.;.;.;
MVP		0.57
MPC		0.13
ClinPred		0.035	T
GERP RS		-2.2
Varity_R		0.14
gMVP		0.81

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: rs79149180; hg19: chr5-110097362;