chr17-81715568-A-T

Variant names:

• chr17-81715568-A-T
• rs1555703272
• NM_012140.5:c.304A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_012140.5(SLC25A10):​c.304A>T​(p.Lys102*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001571204: Well-established functional studies show a deleterious effect (PS3 downgraded to moderate).". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC25A10 NM_012140.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.25
• Publications: 0 publications found

Genes affected

SLC25A10 (HGNC:10980): (solute carrier family 25 member 10) This gene encodes a member of a family of proteins that translocate small metabolites across the mitochondrial membrane. The encoded protein exchanges dicarboxylates, such as malate and succinate, for phosphate, sulfate, and other small molecules, thereby providing substrates for metabolic processes including the Krebs cycle and fatty acid synthesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

SLC25A10 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 19

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000262660 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001571204: Well-established functional studies show a deleterious effect (PS3 downgraded to moderate).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-81715568-A-T is Pathogenic according to our data. Variant chr17-81715568-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012140.5. 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
	SLC25A10	NM_012140.5	MANE Select	c.304A>T	p.Lys102*	stop_gained	Exon 3 of 11	NP_036272.2
	SLC25A10	NM_001270953.2		c.304A>T	p.Lys102*	stop_gained	Exon 3 of 11	NP_001257882.1	F6RGN5
	SLC25A10	NM_001270888.2		c.304A>T	p.Lys102*	stop_gained	Exon 3 of 11	NP_001257817.1	Q9UBX3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A10	ENST00000350690.10	TSL:1 MANE Select	c.304A>T	p.Lys102*	stop_gained	Exon 3 of 11	ENSP00000345580.5	Q9UBX3-1
	ENSG00000262660	ENST00000571730.1	TSL:2	c.769A>T	p.Lys257*	stop_gained	Exon 7 of 15	ENSP00000461324.1	B4DLN1
	SLC25A10	ENST00000545862.5	TSL:1	c.304A>T	p.Lys102*	stop_gained	Exon 3 of 11	ENSP00000446242.2	F6RGN5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial DNA depletion syndrome 19 (2)
1	-	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		8.2
Vest4		0.31
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: -2

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

Other links and lift over

dbSNP: rs1555703272; hg19: chr17-79682598;