rs6728344

chr2-227702330-T-Cchr2-227702330-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025243.4(SLC19A3):c.-2-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,316 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (265 hom., cov: 32)
  • Exomes 𝑓: 0.012 (323 hom.)
• Consequence: SLC19A3 NM_025243.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005165
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.546

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-227702330-T-C is Benign according to our data. Variant chr2-227702330-T-C is described in ClinVar as [Benign]. Clinvar id is 139122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227702330-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A3	NM_025243.4	c.-2-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A3	ENST00000644224.2	c.-2-10A>G		splice_polypyrimidine_tract_variant, intron_variant			NM_025243.4	P1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5620 AN: 151766 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0327

GnomAD3 exomes AF: 0.0153 AC: 3840 AN: 251086 Hom.: 112 AF XY: 0.0133 AC XY: 1809 AN XY: 135724

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00464

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0122 AC: 17837 AN: 1461446 Hom.: 323 Cov.: 31 AF XY: 0.0115 AC XY: 8360 AN XY: 727042

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00423

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0371 AC: 5634 AN: 151870 Hom.: 265 Cov.: 32 AF XY: 0.0367 AC XY: 2726 AN XY: 74196

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.000285

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0328

Alfa AF: 0.0239 Hom.: 39

Bravo AF: 0.0424

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Biotin-responsive basal ganglia disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.6
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.076
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

LitVar

Other links and lift over

dbSNP: rs6728344; hg19: chr2-228567046;