NM_025243.4:c.20C>A

Variant names:

• chr2-227702299-G-T
• rs713993048
• NM_025243.4:c.20C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_025243.4(SLC19A3):​c.20C>A​(p.Ser7*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC19A3 NM_025243.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.430
• Publications: 11 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 72 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-227702299-G-T is Pathogenic according to our data. Variant chr2-227702299-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 162137.Status of the report is criteria_provided_single_submitter, 1 stars.

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.20C>A	p.Ser7*	stop_gained	Exon 2 of 6	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.20C>A	p.Ser7*	stop_gained	Exon 2 of 6	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.20C>A	p.Ser7*	stop_gained	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.20C>A	p.Ser7*	stop_gained	Exon 2 of 6	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.20C>A	p.Ser7*	stop_gained	Exon 2 of 6	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000419059.1	TSL:1	c.20C>A	p.Ser7*	stop_gained	Exon 1 of 2	ENSP00000398349.1	C9J4J5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.43
Vest4		0.70
GERP RS		2.9
Mutation Taster		=14/186	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs713993048; hg19: chr2-228567015;