rs200276538

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001126121.2(SLC25A19):c.622C>T(p.Pro208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,613,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

SLC25A19
NM_001126121.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.36

Publications

2 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 Gene-Disease associations (from GenCC):

Amish lethal microcephaly
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
progressive demyelinating neuropathy with bilateral striatal necrosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC25A19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15283394).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126121.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A19	NM_001126121.2	MANE Select	c.622C>T	p.Pro208Ser	missense	Exon 6 of 8	NP_001119593.1
SLC25A19	NM_001126122.2		c.622C>T	p.Pro208Ser	missense	Exon 5 of 7	NP_001119594.1
SLC25A19	NM_021734.5		c.622C>T	p.Pro208Ser	missense	Exon 6 of 8	NP_068380.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A19	ENST00000416858.7	TSL:1 MANE Select	c.622C>T	p.Pro208Ser	missense	Exon 6 of 8	ENSP00000397818.2
SLC25A19	ENST00000402418.7	TSL:1	c.622C>T	p.Pro208Ser	missense	Exon 4 of 6	ENSP00000385312.3
SLC25A19	ENST00000320362.7	TSL:2	c.622C>T	p.Pro208Ser	missense	Exon 7 of 9	ENSP00000319574.3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251346

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000331

AC:

484

AN:

1461592

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

237

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.000400

AC:

445

AN:

1112004

Other (OTH)

AF:

0.000398

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41414

American (AMR)

AF:

0.000197

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000374

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Amish lethal microcephaly (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.12

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Benign

0.069

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.5

PhyloP100

5.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.38

Sift

Benign

0.11

Sift4G

Benign

0.71

Polyphen

0.029

Vest4

0.37

MVP

0.72

MPC

0.15

ClinPred

0.058

GERP RS

5.6

Varity_R

0.053

gMVP

0.69

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over