Genetic Variant SLC19A3:p.Gln267Gln (chr2-227698914-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_025243.4(SLC19A3):c.801A>G(p.Gln267Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000797 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SLC19A3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 1 hom. )

Consequence

SLC19A3
NM_025243.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.436

Publications

1 publications found

Variant links:

Genes affected

SLC19A3 (HGNC:16266): (solute carrier family 19 member 3) This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke's-like encephalopathy.[provided by RefSeq, Jan 2010]

SLC19A3 Gene-Disease associations (from GenCC):

biotin-responsive basal ganglia disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thiamine-responsive encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC19A3 links:

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ACMG classification

Specifications for SLC19A3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-227698914-T-C is Benign according to our data. Variant chr2-227698914-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281501.

BP7

Synonymous conserved (PhyloP=-0.436 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000683 (104/152316) while in subpopulation SAS AF = 0.00104 (5/4828). AF 95% confidence interval is 0.000795. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025243.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A3	NM_025243.4	MANE Select	c.801A>G	p.Gln267Gln	synonymous	Exon 3 of 6	NP_079519.1	Q9BZV2
SLC19A3	NM_001371411.1		c.801A>G	p.Gln267Gln	synonymous	Exon 3 of 6	NP_001358340.1	Q9BZV2
SLC19A3	NM_001371412.1		c.801A>G	p.Gln267Gln	synonymous	Exon 3 of 6	NP_001358341.1	Q9BZV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A3	ENST00000644224.2	MANE Select	c.801A>G	p.Gln267Gln	synonymous	Exon 3 of 6	ENSP00000495385.1	Q9BZV2
SLC19A3	ENST00000258403.8	TSL:1	c.801A>G	p.Gln267Gln	synonymous	Exon 3 of 6	ENSP00000258403.3	Q9BZV2
SLC19A3	ENST00000425817.6	TSL:1	n.*826A>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000696

AC:

175

AN:

251348

AF XY:

0.000766

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.000836

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000809

AC:

1182

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000810

AC XY:

589

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.000246

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000730

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000848

AC:

943

AN:

1111952

Other (OTH)

AF:

0.000844

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000683

AC:

104

AN:

152316

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41580

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000899

Hom.:

Bravo

AF:

0.000593

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Biotin-responsive basal ganglia disease (3)

not provided (3)

not specified (1)

SLC19A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.0

(source)

DANN

Benign

0.38

PhyloP100

-0.44

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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