rs758140632

chr5-110739315-G-Achr5-110739315-G-T

Variant summary

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

The NM_138773.4(SLC25A46):c.196G>A(p.Val66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,416,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21

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=0.187673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.196G>A	p.Val66Met	missense_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.196G>A	p.Val66Met	missense_variant	1/8
SLC25A46	NM_001303250.3	c.10+1068G>A		intron_variant
SLC25A46	NR_138151.2	n.309G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.196G>A	p.Val66Met	missense_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.196G>A	p.Val66Met	missense_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+1068G>A		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+1068G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000571 AC: 1 AN: 175202 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 93906

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: 0.0000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1416874 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 700704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000842 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0065	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.20
Sift	Benign	0.095	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.30	B;.
Vest4		0.11
MutPred		0.072		Loss of catalytic residue at V66 (P = 0.0261);Loss of catalytic residue at V66 (P = 0.0261);
MVP		0.69
MPC		0.094
ClinPred		0.53	D
GERP RS		3.2
Varity_R		0.085
gMVP		0.27

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: rs758140632; hg19: chr5-110075016;