5-110739145-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.26T>A	p.Phe9Tyr	missense_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.26T>A	p.Phe9Tyr	missense_variant	1/8
SLC25A46	NM_001303250.3	c.10+898T>A		intron_variant
SLC25A46	NR_138151.2	n.139T>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.26T>A	p.Phe9Tyr	missense_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.26T>A	p.Phe9Tyr	missense_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+898T>A		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+898T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.26T>A (p.F9Y) alteration is located in exon 1 (coding exon 1) of the SLC25A46 gene. This alteration results from a T to A substitution at nucleotide position 26, causing the phenylalanine (F) at amino acid position 9 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.64	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		0.40	B;.
Vest4		0.61
MutPred		0.34		Gain of phosphorylation at F9 (P = 0.012);Gain of phosphorylation at F9 (P = 0.012);
MVP		0.58
MPC		0.34
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.61
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-110074846;