NM_001126121.2:c.*2T>C

Variant names:

• chr17-75273449-A-G
• rs1809352
• NM_001126121.2:c.*2T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126121.2(SLC25A19):​c.*2T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 1,613,434 control chromosomes in the GnomAD database, including 685,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59952 hom., cov: 36)
  • Exomes 𝑓: 0.92 (625901 hom.)
• Consequence: SLC25A19 NM_001126121.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.842
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-75273449-A-G is Benign according to our data. Variant chr17-75273449-A-G is described in ClinVar as Benign. ClinVar VariationId is 130327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A19	NM_001126121.2	c.*2T>C		3_prime_UTR_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.*2T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_001126121.2	ENSP00000397818.2

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134581 AN: 152212 Hom.: 59922 Cov.: 36

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.915

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.882

GnomAD2 exomes AF: 0.930 AC: 231799 AN: 249178 AF XY: 0.934

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.955

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.917

GnomAD4 exome AF: 0.925 AC: 1351340 AN: 1461104 Hom.: 625901 Cov.: 49 AF XY: 0.927 AC XY: 673655 AN XY: 726828

African (AFR) AF: 0.759 AC: 25396 AN: 33468

American (AMR) AF: 0.941 AC: 42072 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 23470 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39698

South Asian (SAS) AF: 0.978 AC: 84344 AN: 86236

European-Finnish (FIN) AF: 0.956 AC: 50693 AN: 53004

Middle Eastern (MID) AF: 0.843 AC: 4816 AN: 5712

European-Non Finnish (NFE) AF: 0.922 AC: 1025511 AN: 1111790

Other (OTH) AF: 0.917 AC: 55353 AN: 60374

GnomAD4 genome AF: 0.884 AC: 134663 AN: 152330 Hom.: 59952 Cov.: 36 AF XY: 0.889 AC XY: 66212 AN XY: 74490

African (AFR) AF: 0.768 AC: 31911 AN: 41548

American (AMR) AF: 0.915 AC: 14001 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3090 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5182 AN: 5186

South Asian (SAS) AF: 0.977 AC: 4723 AN: 4834

European-Finnish (FIN) AF: 0.954 AC: 10135 AN: 10626

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.921 AC: 62630 AN: 68034

Other (OTH) AF: 0.882 AC: 1867 AN: 2116

Alfa AF: 0.912 Hom.: 76776

Bravo AF: 0.876

Asia WGS AF: 0.967 AC: 3363 AN: 3478

EpiCase AF: 0.918

EpiControl AF: 0.921

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Feb 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

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 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	-0.83
CADD	Benign	0.86
DANN	Benign	0.64
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1809352; hg19: chr17-73269530;