rs35220834

chr5-110746313-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_138773.4(SLC25A46):c.429C>T(p.Val143=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00984 in 1,592,252 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (194 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (208 hom.)
• Consequence: SLC25A46 NM_138773.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.329

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-110746313-C-T is Benign according to our data. Variant chr5-110746313-C-T is described in ClinVar as [Benign]. Clinvar id is 475796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110746313-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.329 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.429C>T	p.Val143=	synonymous_variant	4/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.429C>T	p.Val143=	synonymous_variant	4/8
SLC25A46	NM_001303250.3	c.156C>T	p.Val52=	synonymous_variant	4/8
SLC25A46	NR_138151.2	n.542C>T		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.429C>T	p.Val143=	synonymous_variant	4/8	1	NM_138773.4	P1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4606 AN: 152086 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0939

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00685

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.00973 AC: 2238 AN: 229912 Hom.: 70 AF XY: 0.00812 AC XY: 1015 AN XY: 125030

Gnomad AFR exome AF: 0.0893

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000636

Gnomad FIN exome AF: 0.00108

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.00768 AC: 11059 AN: 1440050 Hom.: 208 Cov.: 28 AF XY: 0.00722 AC XY: 5172 AN XY: 716524

Gnomad4 AFR exome AF: 0.0960

Gnomad4 AMR exome AF: 0.00728

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.0000263

Gnomad4 SAS exome AF: 0.000873

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.00620

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0303 AC: 4613 AN: 152202 Hom.: 194 Cov.: 32 AF XY: 0.0288 AC XY: 2141 AN XY: 74416

Gnomad4 AFR AF: 0.0939

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00682

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0164 Hom.: 44

Bravo AF: 0.0352

Asia WGS AF: 0.00608 AC: 21 AN: 3468

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

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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
BayesDel_noAF	Benign	-0.38
Cadd	Benign	9.2
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35220834; hg19: chr5-110082014;