14-37172308-G-A

Variant names:

• chr14-37172308-G-A
• NM_030631.4:c.43C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030631.4(SLC25A21):​c.43C>T​(p.Arg15Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,449,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC25A21 NM_030631.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.956

Genes affected

SLC25A21 (HGNC:14411): (solute carrier family 25 member 21) SLC25A21 is a homolog of the S. cerevisiae ODC proteins, mitochondrial carriers that transport C5-C7 oxodicarboxylates across inner mitochondrial membranes. One of the species transported by ODC is 2-oxoadipate, a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine in mammals. Within mitochondria, 2-oxoadipate is converted into acetyl-CoA.[supplied by OMIM, Apr 2004]

SLC25A21-AS1 (HGNC:44298): (SLC25A21 antisense RNA 1)

ACMG classification

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=0.23987952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A21	NM_030631.4	c.43C>T	p.Arg15Trp	missense_variant	Exon 1 of 10	ENST00000331299.6	NP_085134.1
SLC25A21	NM_001171170.2	c.43C>T	p.Arg15Trp	missense_variant	Exon 1 of 11		NP_001164641.1
SLC25A21	XM_047431871.1	c.43C>T	p.Arg15Trp	missense_variant	Exon 1 of 9		XP_047287827.1
SLC25A21-AS1	NR_033240.1	n.283G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A21	ENST00000331299.6	c.43C>T	p.Arg15Trp	missense_variant	Exon 1 of 10	1	NM_030631.4	ENSP00000329452.5
SLC25A21	ENST00000555449.5	c.43C>T	p.Arg15Trp	missense_variant	Exon 1 of 11	2		ENSP00000451873.1
SLC25A21-AS1	ENST00000556667.1	n.421G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
SLC25A21	ENST00000557611.1	n.39C>T		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1449890 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719904

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: 0.00000723

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 18 Uncertain:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.43C>T (p.Arg15Trp) variant in the SLC25A21 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Arginine at position 15 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen-Benign, SIFT-Tolerated and MutationTaster-Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Arginine in SLC25A21 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.0080	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.063	.;B
Vest4		0.55
MutPred		0.61		Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);
MVP		0.86
MPC		0.31
ClinPred		0.67	D
GERP RS		1.3
Varity_R		0.054
gMVP		0.65

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: chr14-37641513;