14-36684769-T-A

Variant names:

• chr14-36684769-T-A
• rs778076388
• NM_030631.4:c.760A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030631.4(SLC25A21):​c.760A>T​(p.Met254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M254I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A21 NM_030631.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• Publications: 0 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39991045).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030631.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A21	NM_030631.4	MANE Select	c.760A>T	p.Met254Leu	missense	Exon 8 of 10	NP_085134.1	Q9BQT8-1
	SLC25A21	NM_001171170.2		c.760A>T	p.Met254Leu	missense	Exon 8 of 11	NP_001164641.1	Q9BQT8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A21	ENST00000331299.6	TSL:1 MANE Select	c.760A>T	p.Met254Leu	missense	Exon 8 of 10	ENSP00000329452.5	Q9BQT8-1
	SLC25A21	ENST00000555449.5	TSL:2	c.760A>T	p.Met254Leu	missense	Exon 8 of 11	ENSP00000451873.1	Q9BQT8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.49	N
PhyloP100		7.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.26
Sift	Benign	0.33	T
Sift4G	Benign	0.58	T
Polyphen		0.0030	B
Vest4		0.61
MutPred		0.55		Gain of ubiquitination at K252 (P = 0.1472)
MVP		0.49
MPC		0.14
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.38
gMVP		0.80
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs778076388; hg19: chr14-37153974;