chr22-19176228-C-T

Position:

• chr22-19176228-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005984.5(SLC25A1):​c.838G>A​(p.Val280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC25A1 NM_005984.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0580

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 2 ACMG points.

• PM1: In a transmembrane_region Helical; Name=6 (size 19) in uniprot entity TXTP_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005984.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11145216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A1	NM_005984.5	c.838G>A	p.Val280Ile	missense_variant	9/9	ENST00000215882.10	NP_005975.1
SLC25A1	NM_001256534.2	c.859G>A	p.Val287Ile	missense_variant	8/8		NP_001243463.1
SLC25A1	NM_001287387.2	c.529G>A	p.Val177Ile	missense_variant	9/9		NP_001274316.1
SLC25A1	NR_046298.3	n.762G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A1	ENST00000215882.10	c.838G>A	p.Val280Ile	missense_variant	9/9	1	NM_005984.5	ENSP00000215882	P1
SLC25A1	ENST00000451283.5	c.529G>A	p.Val177Ile	missense_variant	9/9	2		ENSP00000401480
SLC25A1	ENST00000470922.5	n.980G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250638 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460678 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726676

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2021

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SLC25A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 280 of the SLC25A1 protein (p.Val280Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.7
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.23	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.12
Sift	Benign	0.35	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.013	B;.
Vest4		0.15
MutPred		0.63		Loss of methylation at R282 (P = 0.1412);.;
MVP		0.15
MPC		0.39
ClinPred		0.15	T
GERP RS		3.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.049
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1234366257; hg19: chr22-19163741;