rs34080459

Variant names:

• chr2-227702277-G-A
• rs34080459
• NM_025243.4:c.42C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025243.4(SLC19A3):​c.42C>T​(p.Tyr14Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,048 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: SLC19A3 NM_025243.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.23
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-227702277-G-A is Benign according to our data. Variant chr2-227702277-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	NM_025243.4	MANE Select	c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	NP_001358341.1	Q9BZV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	ENST00000644224.2	MANE Select	c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000419059.1	TSL:1	c.42C>T	p.Tyr14Tyr	synonymous	Exon 1 of 2	ENSP00000398349.1	C9J4J5

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2314 AN: 152172 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00391 AC: 982 AN: 251406 AF XY: 0.00300

Gnomad AFR exome AF: 0.0546

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00151 AC: 2207 AN: 1461758 Hom.: 46 Cov.: 31 AF XY: 0.00127 AC XY: 926 AN XY: 727192

African (AFR) AF: 0.0535 AC: 1792 AN: 33470

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000710 AC: 79 AN: 1111908

Other (OTH) AF: 0.00361 AC: 218 AN: 60396

GnomAD4 genome AF: 0.0153 AC: 2326 AN: 152290 Hom.: 59 Cov.: 32 AF XY: 0.0148 AC XY: 1102 AN XY: 74466

African (AFR) AF: 0.0529 AC: 2196 AN: 41544

American (AMR) AF: 0.00608 AC: 93 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00752 Hom.: 27

Bravo AF: 0.0172

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Biotin-responsive basal ganglia disease (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.6
DANN	Benign	0.41
PhyloP100		1.2
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs34080459; hg19: chr2-228566993;