rs864321624

Variant names:

• chr19-19110790-A-G
• rs864321624
• NM_178526.5:c.871A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_178526.5(SLC25A42):​c.871A>G​(p.Asn291Asp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A42 NM_178526.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.34
• Publications: 8 publications found

Genes affected

SLC25A42 (HGNC:28380): (solute carrier family 25 member 42) This gene encodes a solute carrier family 25 protein. Solute carrier family 25 proteins are localized to mitochondria and play critical roles in the transport of molecules across the inner mitochondrial membrane. The encoded protein is a mitochondrial transporter for coenzyme A (CoA) and adenosine 3',5'-diphosphate. [provided by RefSeq, Feb 2012]

SLC25A42 Gene-Disease associations (from GenCC):

• metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 19-19110790-A-G is Pathogenic according to our data. Variant chr19-19110790-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178526.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A42	NM_178526.5	MANE Select	c.871A>G	p.Asn291Asp	missense	Exon 8 of 8	NP_848621.2
	SLC25A42	NM_001321544.2		c.871A>G	p.Asn291Asp	missense	Exon 8 of 8	NP_001308473.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A42	ENST00000318596.8	TSL:1 MANE Select	c.871A>G	p.Asn291Asp	missense	Exon 8 of 8	ENSP00000326693.6
	SLC25A42	ENST00000596819.1	TSL:2	n.*144A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression (10)
1	-	-	Inborn mitochondrial myopathy (1)
1	-	-	SLC25A42-related mitochondrial disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		8.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Loss of MoRF binding (P = 0.0434)
MVP		0.82
MPC		2.8
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.98
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs864321624; hg19: chr19-19221599;