17-75273449-A-G

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126121.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A19	NM_001126121.2	MANE Select	c.*2T>C		3_prime_UTR	Exon 8 of 8	NP_001119593.1	Q9HC21-1
	SLC25A19	NM_001126122.2		c.*2T>C		3_prime_UTR	Exon 7 of 7	NP_001119594.1	Q9HC21-1
	SLC25A19	NM_021734.5		c.*2T>C		3_prime_UTR	Exon 8 of 8	NP_068380.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A19	ENST00000416858.7	TSL:1 MANE Select	c.*2T>C		3_prime_UTR	Exon 8 of 8	ENSP00000397818.2	Q9HC21-1
	SLC25A19	ENST00000402418.7	TSL:1	c.*2T>C		3_prime_UTR	Exon 6 of 6	ENSP00000385312.3	Q9HC21-1
	SLC25A19	ENST00000320362.7	TSL:2	c.*2T>C		3_prime_UTR	Exon 9 of 9	ENSP00000319574.3	Q9HC21-1

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Amish lethal microcephaly (2)
-	-	2	not specified (2)
-	-	1	Progressive demyelinating neuropathy with bilateral striatal necrosis (1)

Computational scores

Source: dbNSFP v4.9

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;