Genetic Variant SLC25A19:c.*200G>A (chr17-75273251-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001126121.2(SLC25A19):c.*200G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 607,638 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 10 hom., cov: 34)

Exomes 𝑓: 0.00091 ( 8 hom. )

Consequence

SLC25A19
NM_001126121.2 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.128

Publications

0 publications found

Variant links:

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 links:

MIF4GD-DT (HGNC:55335): (MIF4GD divergent transcript)

MIF4GD-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 17-75273251-C-T is Benign according to our data. Variant chr17-75273251-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1078/152334) while in subpopulation AFR AF = 0.0246 (1023/41580). AF 95% confidence interval is 0.0234. There are 10 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC25A19	NM_001126121.2	MANE Select	c.*200G>A	3_prime_UTR	Exon 8 of 8	NP_001119593.1	Q9HC21-1
SLC25A19	NM_001126122.2		c.*200G>A	3_prime_UTR	Exon 7 of 7	NP_001119594.1	Q9HC21-1
SLC25A19	NM_021734.5		c.*200G>A	3_prime_UTR	Exon 8 of 8	NP_068380.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A19	ENST00000416858.7	TSL:1 MANE Select	c.*200G>A		3_prime_UTR	Exon 8 of 8	ENSP00000397818.2	Q9HC21-1
SLC25A19	ENST00000402418.7	TSL:1	c.*200G>A		3_prime_UTR	Exon 6 of 6	ENSP00000385312.3	Q9HC21-1
SLC25A19	ENST00000582822.1	TSL:3	c.188G>A	p.Arg63His	missense	Exon 3 of 3	ENSP00000462401.1	J3KSB1

Frequencies

GnomAD3 genomes

AF:

0.00706

AC:

1074

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00284

AC:

170

AN:

59914

AF XY:

0.00237

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000911

AC:

415

AN:

455304

Hom.:

Cov.:

AF XY:

0.000796

AC XY:

192

AN XY:

241144

show subpopulations

African (AFR)

AF:

0.0255

AC:

325

AN:

12738

American (AMR)

AF:

0.00135

AC:

AN:

19208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13704

East Asian (EAS)

AF:

0.00

AC:

AN:

30512

South Asian (SAS)

AF:

0.000107

AC:

AN:

46530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28236

Middle Eastern (MID)

AF:

0.00150

AC:

AN:

1994

European-Non Finnish (NFE)

AF:

0.0000615

AC:

AN:

276320

Other (OTH)

AF:

0.00150

AC:

AN:

26062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00708

AC:

1078

AN:

152334

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

508

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0246

AC:

1023

AN:

41580

American (AMR)

AF:

0.00196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00360

Hom.:

Bravo

AF:

0.00814

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amish lethal microcephaly (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.41

(source)

DANN

Benign

0.67

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over