rs372409562

Variant names:

• chr17-44321193-G-A
• rs372409562
• NM_001143780.3:c.556C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44321193-G-A
• chr17-44321193-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001143780.3(SLC25A39):​c.556C>T​(p.Arg186Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,372 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SLC25A39 NM_001143780.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A39	NM_001143780.3	c.556C>T	p.Arg186Trp	missense_variant	Exon 8 of 12	ENST00000377095.10	NP_001137252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A39	ENST00000377095.10	c.556C>T	p.Arg186Trp	missense_variant	Exon 8 of 12	1	NM_001143780.3	ENSP00000366299.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248720 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1460202 Hom.: 0 Cov.: 33 AF XY: 0.0000317 AC XY: 23 AN XY: 726402

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111542

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556C>T (p.R186W) alteration is located in exon 8 (coding exon 7) of the SLC25A39 gene. This alteration results from a C to T substitution at nucleotide position 556, causing the arginine (R) at amino acid position 186 to be replaced by a tryptophan (W). 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	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;D;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.4	.;H;.;.;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D;D;.;.;D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Uncertain	0.051	T;T;T;T;D;T
Polyphen		1.0	D;P;D;.;D;.
Vest4		0.98
MVP		0.88
MPC		0.30
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.91
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372409562; hg19: chr17-42398561;