rs117864472

chr2-227695929-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025243.4(SLC19A3):c.1132A>G(p.Ile378Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,614,094 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (17 hom.)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.949

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 (MetaRNN=0.008207351).
• BP6: Variant 2-227695929-T-C is Benign according to our data. Variant chr2-227695929-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 334878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227695929-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000907 (138/152220) while in subpopulation EAS AF= 0.0228 (118/5176). AF 95% confidence interval is 0.0195. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A3	NM_025243.4	c.1132A>G	p.Ile378Val	missense_variant	4/6	ENST00000644224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A3	ENST00000644224.2	c.1132A>G	p.Ile378Val	missense_variant	4/6		NM_025243.4	P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152102 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00198 AC: 498 AN: 251474 Hom.: 3 AF XY: 0.00194 AC XY: 263 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0248

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000729 AC: 1065 AN: 1461874 Hom.: 17 Cov.: 30 AF XY: 0.000771 AC XY: 561 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000907 AC: 138 AN: 152220 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74412

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00131 Hom.: 3

Bravo AF: 0.00134

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotin-responsive basal ganglia disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

SLC19A3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	1.4
Dann	Benign	0.70
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.35	T
Polyphen		0.019	B;B;.
Vest4		0.10
MVP		0.46
MPC		0.054
ClinPred		0.0048	T
GERP RS		-4.9
Varity_R		0.023
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs117864472; hg19: chr2-228560645; COSMIC: COSV51453021; COSMIC: COSV51453021;