5-110739132-C-T

Variant names:

• chr5-110739132-C-T
• rs778529430
• NM_138773.4:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138773.4(SLC25A46):​c.13C>T​(p.Arg5Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,395,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R5L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.47
• Publications: 0 publications found

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]

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	NM_138773.4	MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.13C>T	p.Arg5Cys	missense	Exon 1 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.10+885C>T		intron	N/A	NP_001290179.1	B4DY98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.13C>T	p.Arg5Cys	missense	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000665 AC: 1 AN: 150370 AF XY: 0.0000125

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395576 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 688412

African (AFR) AF: 0.00 AC: 0 AN: 31510

American (AMR) AF: 0.00 AC: 0 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.00 AC: 0 AN: 79138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4812

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078634

Other (OTH) AF: 0.00 AC: 0 AN: 57858

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.0094
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.019	B
Vest4		0.75
MutPred		0.32		Loss of methylation at R5 (P = 0.0719)
MVP		0.83
MPC		0.41
ClinPred		0.98	D
GERP RS		3.1
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.55
gMVP		0.68
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs778529430; hg19: chr5-110074833;