NM_025243.4:c.1049T>C

Variant names:

• chr2-227696012-A-G
• rs34507036
• NM_025243.4:c.1049T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025243.4(SLC19A3):​c.1049T>C​(p.Val350Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,614,086 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. The gene SLC19A3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.084 (1489 hom., cov: 33)
  • Exomes 𝑓: 0.018 (1437 hom.)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.47
• Publications: 12 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

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036124885).
• BP6: Variant 2-227696012-A-G is Benign according to our data. Variant chr2-227696012-A-G is described in ClinVar as Benign. ClinVar VariationId is 130320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 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.1049T>C	p.Val350Ala	missense	Exon 4 of 6	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.1049T>C	p.Val350Ala	missense	Exon 4 of 6	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.1049T>C	p.Val350Ala	missense	Exon 4 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.1049T>C	p.Val350Ala	missense	Exon 4 of 6	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.1049T>C	p.Val350Ala	missense	Exon 4 of 6	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000425817.6	TSL:1	n.*1074T>C		non_coding_transcript_exon	Exon 6 of 8	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 12713 AN: 152084 Hom.: 1486 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0656

GnomAD2 exomes AF: 0.0296 AC: 7437 AN: 251454 AF XY: 0.0242

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0179 AC: 26168 AN: 1461884 Hom.: 1437 Cov.: 30 AF XY: 0.0166 AC XY: 12040 AN XY: 727244

African (AFR) AF: 0.274 AC: 9177 AN: 33480

American (AMR) AF: 0.0190 AC: 848 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 296 AN: 26134

East Asian (EAS) AF: 0.0225 AC: 892 AN: 39696

South Asian (SAS) AF: 0.00560 AC: 483 AN: 86258

European-Finnish (FIN) AF: 0.00157 AC: 84 AN: 53420

Middle Eastern (MID) AF: 0.0272 AC: 157 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12496 AN: 1112008

Other (OTH) AF: 0.0287 AC: 1735 AN: 60396

GnomAD4 genome AF: 0.0838 AC: 12750 AN: 152202 Hom.: 1489 Cov.: 33 AF XY: 0.0815 AC XY: 6065 AN XY: 74428

African (AFR) AF: 0.266 AC: 11038 AN: 41474

American (AMR) AF: 0.0369 AC: 564 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.0227 AC: 118 AN: 5190

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 814 AN: 68030

Other (OTH) AF: 0.0659 AC: 139 AN: 2110

Alfa AF: 0.0330 Hom.: 1439

Bravo AF: 0.0950

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.264 AC: 1161

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.0344 AC: 4174

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0135

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Biotin-responsive basal ganglia disease (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.25
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.075	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.3	N
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.067
ClinPred		0.0023	T
GERP RS		1.1
Varity_R		0.030
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs34507036; hg19: chr2-228560728; COSMIC: COSV107252564; COSMIC: COSV107252564;