NM_014251.3:c.2T>A

Variant names:

• chr7-96321955-A-T
• rs541276426
• NM_014251.3:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014251.3(SLC25A13):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC25A13 NM_014251.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.23
• Publications: 19 publications found

Genes affected

SLC25A13 (HGNC:10983): (solute carrier family 25 member 13) This gene is a member of the mitochondrial carrier family. The encoded protein contains four EF-hand Ca(2+) binding motifs in the N-terminal domain, and localizes to mitochondria. The protein catalyzes the exchange of aspartate for glutamate and a proton across the inner mitochondrial membrane, and is stimulated by calcium on the external side of the inner mitochondrial membrane. Mutations in this gene result in citrullinemia, type II. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

SLC25A13 Gene-Disease associations (from GenCC):

• citrin deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• citrullinemia, type II, adult-onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• neonatal intrahepatic cholestasis due to citrin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
• citrullinemia type II

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 35 codons. Genomic position: 96277305. Lost 0.051 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-96321955-A-T is Pathogenic according to our data. Variant chr7-96321955-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 593931.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014251.3. 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
	SLC25A13	NM_014251.3	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 18	NP_055066.1	Q9UJS0-1
	SLC25A13	NM_001160210.2		c.2T>A	p.Met1?	start_lost	Exon 1 of 18	NP_001153682.1	Q9UJS0-2
	SLC25A13	NR_027662.2		n.144T>A		non_coding_transcript_exon	Exon 1 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	ENST00000265631.10	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 18	ENSP00000265631.6	Q9UJS0-1
	SLC25A13	ENST00000416240.6	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 18	ENSP00000400101.2	Q9UJS0-2
	SLC25A13	ENST00000856215.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 19	ENSP00000526274.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389132 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 685954

African (AFR) AF: 0.00 AC: 0 AN: 29064

American (AMR) AF: 0.00 AC: 0 AN: 35870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24562

East Asian (EAS) AF: 0.00 AC: 0 AN: 34174

South Asian (SAS) AF: 0.00 AC: 0 AN: 77830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077862

Other (OTH) AF: 0.00 AC: 0 AN: 57578

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Neonatal intrahepatic cholestasis due to citrin deficiency;CN295299:Citrullinemia, type II, adult-onset (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.071
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.056	T
PhyloP100		2.2
PROVEAN	Benign	0.38	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.46	P
Vest4		0.92
MutPred		0.55		Gain of MoRF binding (P = 0.0147)
MVP		0.94
ClinPred		0.95	D
GERP RS		4.0
PromoterAI		-0.51	Under-expression
Varity_R		0.88
gMVP		0.74
Mutation Taster		=9/191	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: rs541276426; hg19: chr7-95951267;