rs145804755

Variant names:

• chr2-227699094-T-C
• rs145804755
• NM_025243.4:c.621A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025243.4(SLC19A3):​c.621A>G​(p.Ile207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,614,128 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: -1.29
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006596446).
• BP6: Variant 2-227699094-T-C is Benign according to our data. Variant chr2-227699094-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215152.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00141 (214/152242) while in subpopulation NFE AF = 0.0027 (184/68044). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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.621A>G	p.Ile207Met	missense	Exon 3 of 6	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.621A>G	p.Ile207Met	missense	Exon 3 of 6	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.621A>G	p.Ile207Met	missense	Exon 3 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.621A>G	p.Ile207Met	missense	Exon 3 of 6	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.621A>G	p.Ile207Met	missense	Exon 3 of 6	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000425817.6	TSL:1	n.*646A>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00127 AC: 320 AN: 251412 AF XY: 0.00119

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00307 AC: 4486 AN: 1461886 Hom.: 8 Cov.: 33 AF XY: 0.00295 AC XY: 2144 AN XY: 727242

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00386 AC: 4293 AN: 1112008

Other (OTH) AF: 0.00240 AC: 145 AN: 60396

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74390

African (AFR) AF: 0.000627 AC: 26 AN: 41460

American (AMR) AF: 0.000196 AC: 3 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00270 AC: 184 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00222 Hom.: 2

Bravo AF: 0.00155

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.00240

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Biotin-responsive basal ganglia disease (5)
-	3	1	not provided (4)
-	-	1	SLC19A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.6
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		0.15	B
Vest4		0.047
MVP		0.42
MPC		0.061
ClinPred		0.0098	T
GERP RS		-9.8
Varity_R		0.051
gMVP		0.089
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs145804755; hg19: chr2-228563810;