rs756258729

Variant names:

• chr5-110743774-G-A
• rs756258729
• NM_138773.4:c.371G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_138773.4(SLC25A46):​c.371G>A​(p.Arg124His) variant causes a missense change. The variant allele was found at a frequency of 0.0000282 in 1,452,418 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.38
• Publications: 2 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

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.371G>A	p.Arg124His	missense	Exon 3 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.371G>A	p.Arg124His	missense	Exon 3 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.98G>A	p.Arg33His	missense	Exon 3 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.371G>A	p.Arg124His	missense	Exon 3 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.371G>A	p.Arg124His	missense	Exon 3 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.371G>A	p.Arg124His	missense	Exon 3 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247914 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 41 AN: 1452418 Hom.: 0 Cov.: 28 AF XY: 0.0000221 AC XY: 16 AN XY: 722836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33220

American (AMR) AF: 0.0000227 AC: 1 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.00 AC: 0 AN: 85000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.0000362 AC: 40 AN: 1106218

Other (OTH) AF: 0.00 AC: 0 AN: 59924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000257662), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Neuropathy, hereditary motor and sensory, type 6B (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.83		Gain of sheet (P = 0.0827)
MVP		0.81
MPC		0.40
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.53
gMVP		0.85
Mutation Taster		=227/73	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs756258729; hg19: chr5-110079475; COSMIC: COSV63507156; COSMIC: COSV63507156;