NM_138773.4:c.26T>A

Variant names:

• chr5-110739145-T-A
• rs1561595610
• NM_138773.4:c.26T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138773.4(SLC25A46):​c.26T>A​(p.Phe9Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. F9S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.26T>A	p.Phe9Tyr	missense	Exon 1 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.26T>A	p.Phe9Tyr	missense	Exon 1 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.10+898T>A		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.26T>A	p.Phe9Tyr	missense	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.26T>A	p.Phe9Tyr	missense	Exon 1 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.26T>A	p.Phe9Tyr	missense	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.041	D
Polyphen		0.40	B
Vest4		0.61
MutPred		0.34		Gain of phosphorylation at F9 (P = 0.012)
MVP		0.58
MPC		0.34
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.61
gMVP		0.42
Mutation Taster		=69/31	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: rs1561595610; hg19: chr5-110074846;