1-9573348-T-C

Variant names:

• chr1-9573348-T-C
• NM_032315.3:c.418T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032315.3(SLC25A33):​c.418T>C​(p.Phe140Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC25A33 NM_032315.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

Genes affected

SLC25A33 (HGNC:29681): (solute carrier family 25 member 33) SLC25A33 belongs to the SLC25 family of mitochondrial carrier proteins (Haitina et al., 2006 [PubMed 16949250]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A33	NM_032315.3	c.418T>C	p.Phe140Leu	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000302692.7	NP_115691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A33	ENST00000302692.7	c.418T>C	p.Phe140Leu	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_032315.3	ENSP00000306328.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418T>C (p.F140L) alteration is located in exon 5 (coding exon 5) of the SLC25A33 gene. This alteration results from a T to C substitution at nucleotide position 418, causing the phenylalanine (F) at amino acid position 140 to be replaced by a leucine (L). 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	0.75
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.091
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.61
Sift	Benign	0.13	T
Sift4G	Benign	0.26	T
Polyphen		0.11	B
Vest4		0.83
MutPred		0.48		Loss of helix (P = 0.2022);
MVP		0.54
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.80

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: chr1-9633406;