rs542566978

Variant names:

• chr2-227698853-C-G
• rs542566978
• NM_025243.4:c.862G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-227698853-C-G
• chr2-227698853-C-T
• chr2-227698853-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025243.4(SLC19A3):​c.862G>C​(p.Ala288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A288T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.62
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

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.862G>C	p.Ala288Pro	missense	Exon 3 of 6	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.862G>C	p.Ala288Pro	missense	Exon 3 of 6	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.862G>C	p.Ala288Pro	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.862G>C	p.Ala288Pro	missense	Exon 3 of 6	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.862G>C	p.Ala288Pro	missense	Exon 3 of 6	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000425817.6	TSL:1	n.*887G>C		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.0047
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.6
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.78		Loss of MoRF binding (P = 0.0568)
MVP		0.92
MPC		0.40
ClinPred		0.99	D
GERP RS		0.22
Varity_R		0.82
gMVP		0.85
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs542566978; hg19: chr2-228563569;