chr17-75273449-A-G

Position:

• chr17-75273449-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 130327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75273449-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.*2T>C		3_prime_UTR_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.2151A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.*2T>C		3_prime_UTR_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.2081A>G		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.930 AC: 231799 AN: 249178 Hom.: 108135 AF XY: 0.934 AC XY: 125981 AN XY: 134840

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 SAS exome AF: 0.979

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

Gnomad4 AFR exome AF: 0.759

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.898

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.978

Gnomad4 FIN exome AF: 0.956

Gnomad4 NFE exome AF: 0.922

Gnomad4 OTH exome AF: 0.917

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

Gnomad4 AFR AF: 0.768

Gnomad4 AMR AF: 0.915

Gnomad4 ASJ AF: 0.890

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.977

Gnomad4 FIN AF: 0.954

Gnomad4 NFE AF: 0.921

Gnomad4 OTH AF: 0.882

Alfa AF: 0.913 Hom.: 65310

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

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Amish lethal microcephaly Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Progressive demyelinating neuropathy with bilateral striatal necrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs1809352; hg19: chr17-73269530;