rs746681765

Variant names:

• chr5-110761543-C-T
• rs746681765
• NM_138773.4:c.1018C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-110761543-C-T
• chr5-110761543-C-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PP3_Strong PP5_Very_Strong

The NM_138773.4(SLC25A46):​c.1018C>T​(p.Arg340Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001381774: Experimental studies have shown that this missense change affects SLC25A46 function (PMID:27543974)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.97
• Publications: 11 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]

SLC25A46 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• pontocerebellar hypoplasia, type 1E

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001381774: Experimental studies have shown that this missense change affects SLC25A46 function (PMID: 27543974).; SCV004177010: Functional studies show less abundant protein expression compared to wild type, indicating that this variant impacts protein stability (Wan J et al., PMID: 27543974).; SCV005418126: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_138773.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 5-110761543-C-T is Pathogenic according to our data. Variant chr5-110761543-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1018C>T	p.Arg340Cys	missense	Exon 8 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.775C>T	p.Arg259Cys	missense	Exon 8 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.745C>T	p.Arg249Cys	missense	Exon 8 of 8	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.1018C>T	p.Arg340Cys	missense	Exon 8 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.1012C>T	p.Arg338Cys	missense	Exon 8 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.775C>T	p.Arg259Cys	missense	Exon 8 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250792 AF XY: 0.0000295

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: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461618 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neuropathy, hereditary motor and sensory, type 6B (4)
2	-	-	Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		4.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.79		Loss of sheet (P = 0.1158)
MVP		0.81
MPC		0.41
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs746681765; hg19: chr5-110097243;