chr14-36684769-T-C

Variant names:

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

Variant summary

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

The NM_030631.4(SLC25A21):​c.760A>G​(p.Met254Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,607,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SLC25A21 NM_030631.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• Publications: 1 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 2 ACMG points.

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

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>G	p.Met254Val	missense	Exon 8 of 10	NP_085134.1	Q9BQT8-1
	SLC25A21	NM_001171170.2		c.760A>G	p.Met254Val	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>G	p.Met254Val	missense	Exon 8 of 10	ENSP00000329452.5	Q9BQT8-1
	SLC25A21	ENST00000555449.5	TSL:2	c.760A>G	p.Met254Val	missense	Exon 8 of 11	ENSP00000451873.1	Q9BQT8-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32

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: 0.00000816 AC: 2 AN: 245212 AF XY: 0.00000755

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1455660 Hom.: 0 Cov.: 31 AF XY: 0.00000967 AC XY: 7 AN XY: 723802

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 84578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1109856

Other (OTH) AF: 0.00 AC: 0 AN: 60090

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.010
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.40	N
PhyloP100		7.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.29	T
Polyphen		0.0090	B
Vest4		0.70
MutPred		0.54		Gain of ubiquitination at K252 (P = 0.1222)
MVP		0.57
MPC		0.13
ClinPred		0.19	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.82
Mutation Taster		=69/31	polymorphism

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: rs778076388; hg19: chr14-37153974;