Genetic Variant NM_001126121.2:c.797T>A (chr17-75273617-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001126121.2(SLC25A19):c.797T>A(p.Met266Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,662 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M266R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC25A19
NM_001126121.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Publications

0 publications found

Variant links:

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]

SLC25A19 links:

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

MIF4GD-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A19	NM_001126121.2 link	c.797T>A	p.Met266Lys	missense_variant	Exon 8 of 8	ENST00000416858.7	NP_001119593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A19	ENST00000416858.7 link	c.797T>A	p.Met266Lys	missense_variant	Exon 8 of 8	1	NM_001126121.2	ENSP00000397818.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460662

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4960

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111842

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.24

.;T;T;T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.63

T;.;.;.;.;T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.0

.;L;L;L;L;L;.

PhyloP100

4.9

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.0

N;N;N;N;N;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.092

T;T;T;T;T;.;.

Sift4G

Benign

0.34

T;T;T;T;T;T;.

Polyphen

0.0010

.;B;B;B;B;B;.

Vest4

0.32

MutPred

0.79

.;Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);.;

MVP

0.70

MPC

0.22

ClinPred

0.13

GERP RS

2.9

Varity_R

0.13

gMVP

0.87

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over