17-75273150-G-A

Position:

• chr17-75273150-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001126121.2(SLC25A19):​c.*301C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 429,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SLC25A19 NM_001126121.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.545

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-75273150-G-A is Benign according to our data. Variant chr17-75273150-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 889456.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.*301C>T		3_prime_UTR_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.1852G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.*301C>T		3_prime_UTR_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.1782G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000285 AC: 79 AN: 277200 Hom.: 0 Cov.: 0 AF XY: 0.000251 AC XY: 37 AN XY: 147684

Gnomad4 AFR exome AF: 0.000963

Gnomad4 AMR exome AF: 0.000869

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.000525

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74500

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000646

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amish lethal microcephaly Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.36

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: rs543638381; hg19: chr17-73269231;