rs1554092069

Variant names:

• chr5-110746311-G-A
• rs1554092069
• NM_138773.4:c.427G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_138773.4(SLC25A46):​c.427G>A​(p.Val143Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V143V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• 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]

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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_138773.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09882966).

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.427G>A	p.Val143Ile	missense	Exon 4 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.427G>A	p.Val143Ile	missense	Exon 4 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.154G>A	p.Val52Ile	missense	Exon 4 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.427G>A	p.Val143Ile	missense	Exon 4 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.427G>A	p.Val143Ile	missense	Exon 4 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.427G>A	p.Val143Ile	missense	Exon 4 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuropathy, hereditary motor and sensory, type 6B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.13	N
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.22
Sift	Benign	0.37	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.34		Loss of catalytic residue at V143 (P = 0.0019)
MVP		0.31
MPC		0.049
ClinPred		0.25	T
GERP RS		2.9
Varity_R		0.017
gMVP		0.33
Mutation Taster		=93/7	polymorphism

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: rs1554092069; hg19: chr5-110082012;