rs142281464

Variant names:

• chr17-75278312-G-A
• rs142281464
• NM_001126121.2:c.483C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001126121.2(SLC25A19):​c.483C>T​(p.Ala161Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,614,056 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: SLC25A19 NM_001126121.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.824
• Publications: 1 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]

SLC25A19 Gene-Disease associations (from GenCC):

• Amish lethal microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• progressive demyelinating neuropathy with bilateral striatal necrosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 17-75278312-G-A is Benign according to our data. Variant chr17-75278312-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.824 with no splicing effect.

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.483C>T	p.Ala161Ala	synonymous	Exon 6 of 8	NP_001119593.1
	SLC25A19	NM_001126122.2		c.483C>T	p.Ala161Ala	synonymous	Exon 5 of 7	NP_001119594.1
	SLC25A19	NM_021734.5		c.483C>T	p.Ala161Ala	synonymous	Exon 6 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.483C>T	p.Ala161Ala	synonymous	Exon 6 of 8	ENSP00000397818.2
	SLC25A19	ENST00000402418.7	TSL:1	c.483C>T	p.Ala161Ala	synonymous	Exon 4 of 6	ENSP00000385312.3
	SLC25A19	ENST00000320362.7	TSL:2	c.483C>T	p.Ala161Ala	synonymous	Exon 7 of 9	ENSP00000319574.3

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152074 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000573 AC: 144 AN: 251124 AF XY: 0.000464

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1461864 Hom.: 1 Cov.: 32 AF XY: 0.000202 AC XY: 147 AN XY: 727234

African (AFR) AF: 0.00591 AC: 198 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112010

Other (OTH) AF: 0.000729 AC: 44 AN: 60394

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152192 Hom.: 1 Cov.: 31 AF XY: 0.00173 AC XY: 129 AN XY: 74430

African (AFR) AF: 0.00650 AC: 270 AN: 41518

American (AMR) AF: 0.00157 AC: 24 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00143 Hom.: 2

Bravo AF: 0.00229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

May 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amish lethal microcephaly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs142281464; hg19: chr17-73274393;