22-19176585-C-T

Position:

chr22-19176585-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_005984.5(SLC25A1):c.740G>A(p.Arg247Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,554 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SLC25A1
NM_005984.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.85

Variant links:

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]

SLC25A1 links:

SLC25A1 (HGNC:):

SLC25A1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Tricarboxylate transport protein, mitochondrial (size 297) in uniprot entity TXTP_HUMAN there are 32 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, 0.983

PP5

Variant 22-19176585-C-T is Pathogenic according to our data. Variant chr22-19176585-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 590940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-19176585-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A1	NM_005984.5 linkuse as main transcript	c.740G>A	p.Arg247Gln	missense_variant	7/9	ENST00000215882.10	NP_005975.1	P53007
SLC25A1	NM_001256534.2 linkuse as main transcript	c.761G>A	p.Arg254Gln	missense_variant	6/8		NP_001243463.1	D9HTE9
SLC25A1	NM_001287387.2 linkuse as main transcript	c.431G>A	p.Arg144Gln	missense_variant	7/9		NP_001274316.1	D3DX16
SLC25A1	NR_046298.3 linkuse as main transcript	n.664G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC25A1	ENST00000215882.10 linkuse as main transcript	c.740G>A	p.Arg247Gln	missense_variant	7/9	1	NM_005984.5	ENSP00000215882.5	P53007
SLC25A1	ENST00000451283.5 linkuse as main transcript	c.431G>A	p.Arg144Gln	missense_variant	7/9	2		ENSP00000401480.1	D3DX16
SLC25A1	ENST00000470922.5 linkuse as main transcript	n.882G>A		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251026

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461330

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 23, presynaptic

Pathogenic:2

Pathogenic, criteria provided, single submitter	reference population	John Walton Muscular Dystrophy Research Centre, Newcastle University	Jun 01, 2019	The p.Arg247Gln variant in SLC25A1 was reported previously in a CMS sib-pair (DOI: 10.3233/JND-140021). We now have identified the same variant in three additional families with similar phenotype, supporting the pathogenicity and the clinical association. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.037

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.98

D;.

Vest4

0.90

MutPred

0.94

Gain of methylation at K245 (P = 0.0999);.;

MVP

0.82

MPC

0.85

ClinPred

0.82

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over