NM_001126121.2:c.819G>A

Variant names:

• chr17-75273595-C-T
• rs4789164
• NM_001126121.2:c.819G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126121.2(SLC25A19):​c.819G>A​(p.Leu273Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,613,246 control chromosomes in the GnomAD database, including 377,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (27005 hom., cov: 33)
  • Exomes 𝑓: 0.68 (350140 hom.)
• Consequence: SLC25A19 NM_001126121.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.289

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-75273595-C-T is Benign according to our data. Variant chr17-75273595-C-T is described in ClinVar as [Benign]. Clinvar id is 130333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75273595-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.289 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A19	NM_001126121.2	c.819G>A	p.Leu273Leu	synonymous_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	c.819G>A	p.Leu273Leu	synonymous_variant	Exon 8 of 8	1	NM_001126121.2	ENSP00000397818.2

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82161 AN: 151972 Hom.: 27009 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.784

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.536

GnomAD3 exomes AF: 0.664 AC: 166961 AN: 251294 Hom.: 58739 AF XY: 0.666 AC XY: 90464 AN XY: 135824

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.861

Gnomad SAS exome AF: 0.629

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.684 AC: 999285 AN: 1461156 Hom.: 350140 Cov.: 65 AF XY: 0.682 AC XY: 495794 AN XY: 726866

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.734

Gnomad4 ASJ exome AF: 0.569

Gnomad4 EAS exome AF: 0.882

Gnomad4 SAS exome AF: 0.626

Gnomad4 FIN exome AF: 0.778

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.540 AC: 82159 AN: 152090 Hom.: 27005 Cov.: 33 AF XY: 0.549 AC XY: 40832 AN XY: 74326

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.854

Gnomad4 SAS AF: 0.611

Gnomad4 FIN AF: 0.784

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.537

Alfa AF: 0.615 Hom.: 14912

Bravo AF: 0.518

Asia WGS AF: 0.644 AC: 2241 AN: 3478

EpiCase AF: 0.664

EpiControl AF: 0.664

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Apr 20, 2017

Athena Diagnostics

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

- -

Mar 03, 2015

GeneDx

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:2

-

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. -

-

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 13, 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	-0.78
CADD	Benign	6.9
DANN	Benign	0.59

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: rs4789164; hg19: chr17-73269676;