rs541276426

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-96321955-A-G
• chr7-96321955-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_014251.3(SLC25A13):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,541,380 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SLC25A13 NM_014251.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:15
• 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: Uncertain_significance. The variant received 3 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.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000578 (88/152252) while in subpopulation EAS AF = 0.0163 (84/5162). AF 95% confidence interval is 0.0135. There are 3 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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>C	p.Met1?	start_lost	Exon 1 of 18	NP_055066.1	Q9UJS0-1
	SLC25A13	NM_001160210.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 18	NP_001153682.1	Q9UJS0-2
	SLC25A13	NR_027662.2		n.144T>C		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>C	p.Met1?	start_lost	Exon 1 of 18	ENSP00000265631.6	Q9UJS0-1
	SLC25A13	ENST00000416240.6	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 18	ENSP00000400101.2	Q9UJS0-2
	SLC25A13	ENST00000856215.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 19	ENSP00000526274.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152140 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000839 AC: 115 AN: 137038 AF XY: 0.000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000565

Gnomad OTH exome AF: 0.000261

GnomAD4 exome AF: 0.000199 AC: 277 AN: 1389128 Hom.: 1 Cov.: 31 AF XY: 0.000219 AC XY: 150 AN XY: 685950

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

American (AMR) AF: 0.0000279 AC: 1 AN: 35870

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

East Asian (EAS) AF: 0.00714 AC: 244 AN: 34170

South Asian (SAS) AF: 0.0000128 AC: 1 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: 0.0000102 AC: 11 AN: 1077862

Other (OTH) AF: 0.000347 AC: 20 AN: 57578

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152252 Hom.: 3 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0163 AC: 84 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000856 Hom.: 0

Bravo AF: 0.000540

ExAC AF: 0.000511 AC: 55

Asia WGS AF: 0.00289 AC: 10 AN: 3472

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
1	1	-	Neonatal intrahepatic cholestasis due to citrin deficiency (2)
-	2	-	Neonatal intrahepatic cholestasis due to citrin deficiency;CN295299:Citrullinemia, type II, adult-onset (2)
-	1	-	Citrin deficiency (1)
-	1	-	Citrullinemia type I (1)
-	1	-	Citrullinemia type II (1)
-	1	-	Citrullinemia, type II, adult-onset (1)
-	1	-	Late-onset citrullinemia (1)
-	1	-	not specified (1)
-	1	-	SLC25A13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.066	T
PhyloP100		2.2
PROVEAN	Benign	0.57	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.012	D
Polyphen		0.46	P
Vest4		0.88
MutPred		0.56		Gain of glycosylation at M1 (P = 0.0152)
MVP		0.93
ClinPred		0.27	T
GERP RS		4.0
PromoterAI		-0.47	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.65
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;