2-73000453-T-C

Position:

• chr2-73000453-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144579.3(SFXN5):​c.446A>G​(p.Tyr149Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,408,364 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SFXN5 NM_144579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

Genes affected

SFXN5 (HGNC:16073): (sideroflexin 5) Predicted to enable citrate transmembrane transporter activity. Predicted to be involved in citrate transport and mitochondrial transmembrane transport. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SFXN5 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFXN5	NM_144579.3	c.446A>G	p.Tyr149Cys	missense_variant	8/14	ENST00000272433.7	NP_653180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFXN5	ENST00000272433.7	c.446A>G	p.Tyr149Cys	missense_variant	8/14	1	NM_144579.3	ENSP00000272433.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408364 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 695174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.446A>G (p.Y149C) alteration is located in exon 8 (coding exon 8) of the SFXN5 gene. This alteration results from a A to G substitution at nucleotide position 446, causing the tyrosine (Y) at amino acid position 149 to be replaced by a cysteine (C). 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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.91		Loss of phosphorylation at Y149 (P = 0.1127);Loss of phosphorylation at Y149 (P = 0.1127);.;
MVP		0.56
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs1198549443; hg19: chr2-73227582;