chr5-141303047-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031947.4(SLC25A2):​c.819G>A​(p.Met273Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SLC25A2
NM_031947.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77
Variant links:
Genes affected
SLC25A2 (HGNC:22921): (solute carrier family 25 member 2) This intronless gene encodes a protein that localizes to the mitochondrial inner membrane and likely functions as a transporter of small molecules such as ornithine. This gene is located between the protocadherin beta and gamma gene clusters on chromosome 5. [provided by RefSeq, Dec 2014]
TAF7 (HGNC:11541): (TATA-box binding protein associated factor 7) The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0996553).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC25A2NM_031947.4 linkc.819G>A p.Met273Ile missense_variant Exon 1 of 1 ENST00000239451.7 NP_114153.1 Q9BXI2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC25A2ENST00000239451.7 linkc.819G>A p.Met273Ile missense_variant Exon 1 of 1 6 NM_031947.4 ENSP00000239451.4 Q9BXI2
TAF7ENST00000624699.1 linkn.128+17471G>A intron_variant Intron 1 of 2 3
TAF7ENST00000686518.1 linkn.75+17471G>A intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251406
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461866
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
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:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.819G>A (p.M273I) alteration is located in exon 1 (coding exon 1) of the SLC25A2 gene. This alteration results from a G to A substitution at nucleotide position 819, causing the methionine (M) at amino acid position 273 to be replaced by an isoleucine (I). 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
0.37
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
20
DANN
Benign
0.91
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.27
N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.090
N
REVEL
Benign
0.15
Sift
Benign
0.40
T
Sift4G
Benign
0.49
T
Polyphen
0.0030
B
Vest4
0.14
MutPred
0.52
Loss of catalytic residue at M273 (P = 0.0261);
MVP
0.55
MPC
0.20
ClinPred
0.095
T
GERP RS
1.9
Varity_R
0.17
gMVP
0.26

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782312600; hg19: chr5-140682614; API