17-75283543-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001126121.2(SLC25A19):c.339T>C(p.Tyr113Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,613,560 control chromosomes in the GnomAD database, including 777,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 67098 hom., cov: 30)

Exomes 𝑓: 0.99 ( 710666 hom. )

Consequence

SLC25A19
NM_001126121.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0250

Publications

15 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 17-75283543-A-G is Benign according to our data. Variant chr17-75283543-A-G is described in ClinVar as Benign. ClinVar VariationId is 130330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.025 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A19	NM_001126121.2 link	c.339T>C	p.Tyr113Tyr	synonymous_variant	Exon 5 of 8	ENST00000416858.7	NP_001119593.1	Q9HC21-1Q5JPC1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A19	ENST00000416858.7 link	c.339T>C	p.Tyr113Tyr	synonymous_variant	Exon 5 of 8	1	NM_001126121.2	ENSP00000397818.2		Q9HC21-1

Frequencies

GnomAD3 genomes

AF:

0.936

AC:

142253

AN:

152042

Hom.:

67066

Cov.:

show subpopulations

Gnomad AFR

AF:

0.814

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.932

Gnomad ASJ

AF:

0.995

Gnomad EAS

AF:

0.919

Gnomad SAS

AF:

0.921

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.942

GnomAD2 exomes

AF:

0.964

AC:

241384

AN:

250490

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.810

Gnomad AMR exome

AF:

0.950

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

0.920

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.985

AC:

1440157

AN:

1461400

Hom.:

710666

Cov.:

AF XY:

0.984

AC XY:

715553

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.809

AC:

27066

AN:

33470

American (AMR)

AF:

0.948

AC:

42365

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

25974

AN:

26126

East Asian (EAS)

AF:

0.938

AC:

37220

AN:

39694

South Asian (SAS)

AF:

0.923

AC:

79518

AN:

86138

European-Finnish (FIN)

AF:

1.00

AC:

53345

AN:

53346

Middle Eastern (MID)

AF:

0.972

AC:

5602

AN:

5764

European-Non Finnish (NFE)

AF:

0.999

AC:

1110332

AN:

1111810

Other (OTH)

AF:

0.973

AC:

58735

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1139

2278

3417

4556

5695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<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:

0.935

AC:

142338

AN:

152160

Hom.:

67098

Cov.:

AF XY:

0.935

AC XY:

69540

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.814

AC:

33780

AN:

41484

American (AMR)

AF:

0.932

AC:

14231

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

3455

AN:

3472

East Asian (EAS)

AF:

0.919

AC:

4731

AN:

5146

South Asian (SAS)

AF:

0.921

AC:

4450

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10620

AN:

10620

Middle Eastern (MID)

AF:

0.963

AC:

283

AN:

294

European-Non Finnish (NFE)

AF:

0.998

AC:

67890

AN:

68028

Other (OTH)

AF:

0.943

AC:

1988

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

421

843

1264

1686

2107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.976

Hom.:

36769

Bravo

AF:

0.926

Asia WGS

AF:

0.900

AC:

3129

AN:

3478

EpiCase

AF:

0.997

EpiControl

AF:

0.998

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amish lethal microcephaly

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive demyelinating neuropathy with bilateral striatal necrosis

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.12

(source)

DANN

Benign

0.27

PhyloP100

-0.025

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over