14-36711480-T-G

Variant names:

• chr14-36711480-T-G
• rs17105087
• NM_030631.4:c.441A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030631.4(SLC25A21):​c.441A>C​(p.Gln147His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q147Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A21 NM_030631.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 18

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A21	NM_030631.4	c.441A>C	p.Gln147His	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000331299.6	NP_085134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A21	ENST00000331299.6	c.441A>C	p.Gln147His	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_030631.4	ENSP00000329452.5
SLC25A21	ENST00000555449.5	c.441A>C	p.Gln147His	missense_variant, splice_region_variant	Exon 7 of 11	2		ENSP00000451873.1
SLC25A21	ENST00000556444.1	n.113A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.075	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.12	.;B
Vest4		0.49
MutPred		0.48		Gain of disorder (P = 0.1948);Gain of disorder (P = 0.1948);
MVP		0.67
MPC		0.54
ClinPred		0.82	D
GERP RS		-0.47
Varity_R		0.32
gMVP		0.90
Mutation Taster		=42/58	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

Other links and lift over

dbSNP: rs17105087; hg19: chr14-37180685;