chr22-19176222-G-C

Variant names:

• chr22-19176222-G-C
• rs431905509
• NM_005984.5:c.844C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_005984.5(SLC25A1):​c.844C>G​(p.Arg282Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: "SCV003805947: Published functional studies demonstrate a damaging effect: loss of citrate transport activity (Majd et al., 2018)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC25A1 NM_005984.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.93
• Publications: 7 publications found

Genes affected

SLC25A1 (HGNC:10979): (solute carrier family 25 member 1) This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

LINC01311 (HGNC:50503): (long intergenic non-protein coding RNA 1311)

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003805947: Published functional studies demonstrate a damaging effect: loss of citrate transport activity (Majd et al., 2018)
• PM1: In a chain Tricarboxylate transport protein, mitochondrial (size 297) in uniprot entity TXTP_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_005984.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-19176222-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 22-19176222-G-C is Pathogenic according to our data. Variant chr22-19176222-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 42193.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005984.5. 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
	SLC25A1	NM_005984.5	MANE Select	c.844C>G	p.Arg282Gly	missense	Exon 9 of 9	NP_005975.1	P53007
	SLC25A1	NM_001256534.2		c.865C>G	p.Arg289Gly	missense	Exon 8 of 8	NP_001243463.1	D9HTE9
	SLC25A1	NM_001287387.2		c.535C>G	p.Arg179Gly	missense	Exon 9 of 9	NP_001274316.1	D3DX16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A1	ENST00000215882.10	TSL:1 MANE Select	c.844C>G	p.Arg282Gly	missense	Exon 9 of 9	ENSP00000215882.5	P53007
	SLC25A1	ENST00000880508.1		c.883C>G	p.Arg295Gly	missense	Exon 9 of 9	ENSP00000550567.1
	SLC25A1	ENST00000880513.1		c.853C>G	p.Arg285Gly	missense	Exon 9 of 9	ENSP00000550572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460796 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726728

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	D,L-2-hydroxyglutaric aciduria (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.69		Loss of methylation at R282 (P = 0.0391)
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.98
gMVP		0.94
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: rs431905509; hg19: chr22-19163735;