rs387906944

Positions:

• chr17-75283509-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001126121.2(SLC25A19):​c.373G>A​(p.Gly125Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A19 NM_001126121.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a repeat Solcar 2 (size 86) in uniprot entity TPC_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_001126121.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-75283509-C-T is Pathogenic according to our data. Variant chr17-75283509-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30590.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-75283509-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.373G>A	p.Gly125Ser	missense_variant	5/8	ENST00000416858.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.373G>A	p.Gly125Ser	missense_variant	5/8	1	NM_001126121.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive demyelinating neuropathy with bilateral striatal necrosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Amish lethal microcephaly Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Benign	0.82
DEOGEN2	Uncertain	0.65	D;D;D;D;D;T;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;D;D
Polyphen		1.0	D;D;D;D;D;.;.;.;.
Vest4		0.98
MutPred		0.93		Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);.;Gain of glycosylation at G125 (P = 0.0164);Gain of glycosylation at G125 (P = 0.0164);
MVP		0.34
MPC		0.62
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.92

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: rs387906944; hg19: chr17-73279590;