rs201789237

Positions:

• chr5-110761412-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138773.4(SLC25A46):​c.887A>G​(p.Asn296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018678933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.887A>G	p.Asn296Ser	missense_variant	8/8	ENST00000355943.8
SLC25A46	NM_001303250.3	c.614A>G	p.Asn205Ser	missense_variant	8/8
SLC25A46	NM_001303249.3	c.679-35A>G		intron_variant
SLC25A46	NR_138151.2	n.1126A>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.887A>G	p.Asn296Ser	missense_variant	8/8	1	NM_138773.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250528 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000807 AC: 118 AN: 1461524 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000625 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Aug 15, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 296 of the SLC25A46 protein (p.Asn296Ser). This variant is present in population databases (rs201789237, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. ClinVar contains an entry for this variant (Variation ID: 542448). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.055
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.2
DANN	Benign	0.39
DEOGEN2	Benign	0.0046	T;T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.53	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.070
MVP		0.30
MPC		0.047
ClinPred		0.014	T
GERP RS		0.57
Varity_R		0.017
gMVP		0.34

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: rs201789237; hg19: chr5-110097112; COSMIC: COSV63506400; COSMIC: COSV63506400;