rs797045968

Positions:

• chr17-75273625-C-A
• chr17-75273625-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126121.2(SLC25A19):​c.789G>T​(p.Lys263Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC25A19 NM_001126121.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1533648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.789G>T	p.Lys263Asn	missense_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.2327C>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.789G>T	p.Lys263Asn	missense_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.2257C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.8
DANN	Benign	0.65
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T;.;.;.;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.10	N;N;N;N;N;.;.
REVEL	Benign	0.22
Sift	Benign	0.33	T;T;T;T;T;.;.
Sift4G	Benign	0.84	T;T;T;T;T;T;.
Polyphen		0.0020	.;B;B;B;B;B;.
Vest4		0.12
MutPred		0.54		.;Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);.;
MVP		0.38
MPC		0.17
ClinPred		0.79	D
GERP RS		3.1
Varity_R		0.031
gMVP		0.65

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: rs797045968; hg19: chr17-73269706;