rs766116322

Positions:

• chr5-110755521-C-A
• chr5-110755521-C-T

Variant summary

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

The NM_138773.4(SLC25A46):​c.620C>A​(p.Ser207Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000283 in 1,413,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense, splice_region
• Scores: Splicing: ADA: 0.1814
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.620C>A	p.Ser207Tyr	missense_variant, splice_region_variant	6/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.620C>A	p.Ser207Tyr	missense_variant, splice_region_variant	6/8
SLC25A46	NM_001303250.3	c.347C>A	p.Ser116Tyr	missense_variant, splice_region_variant	6/8
SLC25A46	NR_138151.2	n.733C>A		splice_region_variant, non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.620C>A	p.Ser207Tyr	missense_variant, splice_region_variant	6/8	1	NM_138773.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1413250 Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 2 AN XY: 703292

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: 0.00000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 23, 2021

This variant has not been reported in the literature in individuals with SLC25A46-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 207 of the SLC25A46 protein (p.Ser207Tyr). The serine residue is weakly conserved and there is a large physicochemical difference between serine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	.;L;L;.
MutationTaster	Benign	0.57	D;D;D;D;D;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	D;N;N;D
REVEL	Uncertain	0.55
Sift	Benign	0.032	D;D;T;D
Sift4G	Benign	0.070	T;D;D;T
Polyphen		0.87	.;P;.;.
Vest4		0.56
MutPred		0.68		.;Loss of ubiquitination at K206 (P = 0.0853);Loss of ubiquitination at K206 (P = 0.0853);.;
MVP		0.74
MPC		0.27
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.37
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: rs766116322; hg19: chr5-110091221;