17-75273576-C-T

Position:

• chr17-75273576-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001126121.2(SLC25A19):​c.838G>A​(p.Gly280Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,684 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC25A19 NM_001126121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

SLC25A19 (HGNC:14409): (solute carrier family 25 member 19) This gene encodes a mitochondrial protein that is a member of the solute carrier family. Although this protein was initially thought to be the mitochondrial deoxynucleotide carrier involved in the uptake of deoxynucleotides into the matrix of the mitochondria, further studies have demonstrated that this protein instead functions as the mitochondrial thiamine pyrophosphate carrier, which transports thiamine pyrophosphates into mitochondria. Mutations in this gene cause microcephaly, Amish type, a metabolic disease that results in severe congenital microcephaly, severe 2-ketoglutaric aciduria, and death within the first year. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

MIF4GD-DT (HGNC:55335): (MIF4GD divergent transcript)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.838G>A	p.Gly280Ser	missense_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.2278C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.838G>A	p.Gly280Ser	missense_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.2208C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251442 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461684 Hom.: 0 Cov.: 64 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000165 AC: 2

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

Aug 01, 2022

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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SLC25A19-related conditions. This variant is present in population databases (rs561002779, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 280 of the SLC25A19 protein (p.Gly280Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D;D;D;D;D;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;.;.;.;.;D;T
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.3	.;M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.025	D;D;D;D;D;.;.
Sift4G	Uncertain	0.031	D;D;D;D;D;D;.
Polyphen		0.98	.;D;D;D;D;D;.
Vest4		0.73
MutPred		0.93		.;Gain of phosphorylation at G280 (P = 0.0698);Gain of phosphorylation at G280 (P = 0.0698);Gain of phosphorylation at G280 (P = 0.0698);Gain of phosphorylation at G280 (P = 0.0698);Gain of phosphorylation at G280 (P = 0.0698);.;
MVP		0.23
MPC		0.47
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.91

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: rs561002779; hg19: chr17-73269657;