rs368647424

chr22-19177779-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_005984.5(SLC25A1):c.389G>A(p.Gly130Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,610,334 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SLC25A1
NM_005984.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a transmembrane_region Helical; Name=3 (size 14) in uniprot entity TXTP_HUMAN there are 4 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, 0.958

PP5

Variant 22-19177779-C-T is Pathogenic according to our data. Variant chr22-19177779-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42196.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr22-19177779-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A1	NM_005984.5 linkuse as main transcript	c.389G>A	p.Gly130Asp	missense_variant	4/9	ENST00000215882.10
SLC25A1	NM_001256534.2 linkuse as main transcript	c.410G>A	p.Gly137Asp	missense_variant	3/8
SLC25A1	NM_001287387.2 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	4/9
SLC25A1	NR_046298.3 linkuse as main transcript	n.365+163G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SLC25A1	ENST00000215882.10 linkuse as main transcript	c.389G>A	p.Gly130Asp	missense_variant	4/9	1	NM_005984.5	P1
SLC25A1	ENST00000451283.5 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	4/9	2
SLC25A1	ENST00000461267.1 linkuse as main transcript	n.535G>A		non_coding_transcript_exon_variant	3/6	3
SLC25A1	ENST00000470922.5 linkuse as main transcript	n.531G>A		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

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:

0.0000369

AC:

AN:

243716

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000809

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1458106

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725458

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000614

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000831

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000498

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Published functional studies demonstrate a damaging effect on enzyme activity (Majd et al., 2018; Pop et al., 201); This variant is associated with the following publications: (PMID: 29238895, 29031613, 23393310, 26870663) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2021	Experimental studies have shown that this missense change affects SLC25A1 function (PMID: 29031613). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42196). This missense change has been observed in individual(s) with autosomal recessive combined D-2-, L-2-hydroxyglutaric aciduria (PMID: 23393310, 29238895). This variant is present in population databases (rs368647424, gnomAD 0.08%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 130 of the SLC25A1 protein (p.Gly130Asp). -

D,L-2-hydroxyglutaric aciduria

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.34

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

4.0

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.91

MPC

1.5

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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