rs1555922652

chr22-19177191-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005984.5(SLC25A1):c.455A>C(p.His152Pro) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A1 NM_005984.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Tricarboxylate transport protein, mitochondrial (size 297) in uniprot entity TXTP_HUMAN there are 42 pathogenic changes around while only 0 benign (100%) in NM_005984.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A1	NM_005984.5	c.455A>C	p.His152Pro	missense_variant	5/9	ENST00000215882.10
SLC25A1	NM_001256534.2	c.476A>C	p.His159Pro	missense_variant	4/8
SLC25A1	NM_001287387.2	c.146A>C	p.His49Pro	missense_variant	5/9
SLC25A1	NR_046298.3	n.379A>C		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A1	ENST00000215882.10	c.455A>C	p.His152Pro	missense_variant	5/9	1	NM_005984.5	P1
SLC25A1	ENST00000451283.5	c.146A>C	p.His49Pro	missense_variant	5/9	2
SLC25A1	ENST00000461267.1	n.601A>C		non_coding_transcript_exon_variant	4/6	3
SLC25A1	ENST00000470922.5	n.597A>C		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	27
Dann	Benign	0.95
DEOGEN2	Uncertain	0.63	D;T
Eigen	Benign	0.074
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.12	B;.
Vest4		0.71
MutPred		0.69		Loss of sheet (P = 0.1158);.;
MVP		0.88
MPC		0.79
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555922652; hg19: chr22-19164704;