17-75273572-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001126121.2(SLC25A19):c.842T>G(p.Phe281Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: SLC25A19 NM_001126121.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.83

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12640369).
• BP6: Variant 17-75273572-A-C is Benign according to our data. Variant chr17-75273572-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 596497.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A19	NM_001126121.2	c.842T>G	p.Phe281Cys	missense_variant	8/8	ENST00000416858.7
MIF4GD-DT	NR_036520.1	n.2274A>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A19	ENST00000416858.7	c.842T>G	p.Phe281Cys	missense_variant	8/8	1	NM_001126121.2	P1
MIF4GD-DT	ENST00000585075.1	n.2204A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251446 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135900

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461720 Hom.: 0 Cov.: 64 AF XY: 0.0000715 AC XY: 52 AN XY: 727164

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152294 Hom.: 0 Cov.: 34 AF XY: 0.000457 AC XY: 34 AN XY: 74470

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000495

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 12, 2022	- -

Amish lethal microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 30, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SLC25A19-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T;.;.;.;.;T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.028	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;.;.
REVEL	Pathogenic	0.67
Sift	Benign	0.050	D;D;D;D;D;.;.
Sift4G	Uncertain	0.029	D;D;D;D;D;D;.
Polyphen		0.23	.;B;B;B;B;B;.
Vest4		0.30
MVP		0.082
MPC		0.32
ClinPred		0.11	T
GERP RS		1.7
Varity_R		0.28
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138376525; hg19: chr17-73269653;