17-75273177-G-C

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.*274C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 476,366 control chromosomes in the GnomAD database, including 103,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (27210 hom., cov: 32)
  • Exomes 𝑓: 0.67 (76121 hom.)
• Consequence: SLC25A19 NM_001126121.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.833

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=-0.85).
• BP6: Variant 17-75273177-G-C is Benign according to our data. Variant chr17-75273177-G-C is described in ClinVar as [Benign]. Clinvar id is 325062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.*274C>G		3_prime_UTR_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.1879G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.*274C>G		3_prime_UTR_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.1809G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82523 AN: 152008 Hom.: 27214 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.673 AC: 218314 AN: 324240 Hom.: 76121 Cov.: 2 AF XY: 0.671 AC XY: 115705 AN XY: 172360

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.568

Gnomad4 EAS exome AF: 0.878

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.542 AC: 82519 AN: 152126 Hom.: 27210 Cov.: 32 AF XY: 0.552 AC XY: 41042 AN XY: 74368

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.688

Gnomad4 OTH AF: 0.540

Alfa AF: 0.613 Hom.: 3959

Bravo AF: 0.520

Asia WGS AF: 0.652 AC: 2270 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amish lethal microcephaly Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	9.1
Dann	Benign	0.69

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: rs7198; hg19: chr17-73269258;