NM_001126121.2:c.819G>A

Variant names:

• chr17-75273595-C-T
• rs4789164
• NM_001126121.2:c.819G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126121.2(SLC25A19):​c.819G>A​(p.Leu273Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,613,246 control chromosomes in the GnomAD database, including 377,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (27005 hom., cov: 33)
  • Exomes 𝑓: 0.68 (350140 hom.)
• Consequence: SLC25A19 NM_001126121.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.289
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-75273595-C-T is Benign according to our data. Variant chr17-75273595-C-T is described in ClinVar as Benign. ClinVar VariationId is 130333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.289 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A19	NM_001126121.2	MANE Select	c.819G>A	p.Leu273Leu	synonymous	Exon 8 of 8	NP_001119593.1
	SLC25A19	NM_001126122.2		c.819G>A	p.Leu273Leu	synonymous	Exon 7 of 7	NP_001119594.1
	SLC25A19	NM_021734.5		c.819G>A	p.Leu273Leu	synonymous	Exon 8 of 8	NP_068380.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A19	ENST00000416858.7	TSL:1 MANE Select	c.819G>A	p.Leu273Leu	synonymous	Exon 8 of 8	ENSP00000397818.2
	SLC25A19	ENST00000402418.7	TSL:1	c.819G>A	p.Leu273Leu	synonymous	Exon 6 of 6	ENSP00000385312.3
	SLC25A19	ENST00000320362.7	TSL:2	c.819G>A	p.Leu273Leu	synonymous	Exon 9 of 9	ENSP00000319574.3

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82161 AN: 151972 Hom.: 27009 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.784

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.664 AC: 166961 AN: 251294 AF XY: 0.666

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.861

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.684 AC: 999285 AN: 1461156 Hom.: 350140 Cov.: 65 AF XY: 0.682 AC XY: 495794 AN XY: 726866

African (AFR) AF: 0.122 AC: 4080 AN: 33460

American (AMR) AF: 0.734 AC: 32826 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14865 AN: 26132

East Asian (EAS) AF: 0.882 AC: 34999 AN: 39700

South Asian (SAS) AF: 0.626 AC: 53992 AN: 86216

European-Finnish (FIN) AF: 0.778 AC: 41531 AN: 53388

Middle Eastern (MID) AF: 0.478 AC: 2572 AN: 5384

European-Non Finnish (NFE) AF: 0.697 AC: 775199 AN: 1111846

Other (OTH) AF: 0.650 AC: 39221 AN: 60316

GnomAD4 genome AF: 0.540 AC: 82159 AN: 152090 Hom.: 27005 Cov.: 33 AF XY: 0.549 AC XY: 40832 AN XY: 74326

African (AFR) AF: 0.146 AC: 6076 AN: 41518

American (AMR) AF: 0.644 AC: 9851 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1946 AN: 3468

East Asian (EAS) AF: 0.854 AC: 4409 AN: 5160

South Asian (SAS) AF: 0.611 AC: 2948 AN: 4826

European-Finnish (FIN) AF: 0.784 AC: 8301 AN: 10586

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46648 AN: 67932

Other (OTH) AF: 0.537 AC: 1132 AN: 2108

Alfa AF: 0.615 Hom.: 14912

Bravo AF: 0.518

Asia WGS AF: 0.644 AC: 2241 AN: 3478

EpiCase AF: 0.664

EpiControl AF: 0.664

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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	-0.78
CADD	Benign	6.9
DANN	Benign	0.59
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4789164; hg19: chr17-73269676; COSMIC: COSV108081874; COSMIC: COSV108081874;