17-44320041-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001143780.3(SLC25A39):​c.1040T>G​(p.Phe347Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,613,832 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: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SLC25A39
NM_001143780.3 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.04

Publications

0 publications found
Variant links:
Genes affected
SLC25A39 (HGNC:24279): (solute carrier family 25 member 39) This gene encodes a member of the SLC25 transporter or mitochondrial carrier family of proteins. Members of this family are encoded by the nuclear genome while their protein products are usually embedded in the inner mitochondrial membrane and exhibit wide-ranging substrate specificity. Although the encoded protein is currently considered an orphan transporter, this protein is related to other carriers known to transport amino acids. This protein may play a role in iron homeostasis. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC25A39NM_001143780.3 linkc.1040T>G p.Phe347Cys missense_variant Exon 12 of 12 ENST00000377095.10 NP_001137252.1 Q9BZJ4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC25A39ENST00000377095.10 linkc.1040T>G p.Phe347Cys missense_variant Exon 12 of 12 1 NM_001143780.3 ENSP00000366299.4 Q9BZJ4-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152036
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000756
AC:
19
AN:
251392
AF XY:
0.0000662
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461796
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.000358
AC:
16
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53342
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000809
AC:
9
AN:
1112004
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152036
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74256
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41388
American (AMR)
AF:
0.00105
AC:
16
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.000106
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 03, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1040T>G (p.F347C) alteration is located in exon 12 (coding exon 11) of the SLC25A39 gene. This alteration results from a T to G substitution at nucleotide position 1040, causing the phenylalanine (F) at amino acid position 347 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
Benign
0.31
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
.;T;.;.;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
.;D;D;D;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Pathogenic
3.8
.;H;.;.;.;.
PhyloP100
7.0
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.9
D;D;.;.;D;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;.;.;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;D;.
Vest4
0.89
MutPred
0.76
.;Loss of stability (P = 0.1735);.;.;.;.;
MVP
0.96
MPC
0.37
ClinPred
0.98
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.88
gMVP
0.82
Mutation Taster
=14/86
disease causing

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

Other links and lift over

dbSNP: rs768484651; hg19: chr17-42397409; API