2-227699221-G-C

Position:

• chr2-227699221-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025243.4(SLC19A3):​c.494C>G​(p.Ala165Gly) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4083305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A3	NM_025243.4	c.494C>G	p.Ala165Gly	missense_variant	3/6	ENST00000644224.2	NP_079519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2	c.494C>G	p.Ala165Gly	missense_variant	3/6		NM_025243.4	ENSP00000495385	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	.;D;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	.;D;.;.
Sift4G	Benign	0.20	.;T;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.21
MutPred		0.47		Loss of stability (P = 0.0537);Loss of stability (P = 0.0537);.;.;
MVP		0.77
MPC		0.14
ClinPred		0.71	D
GERP RS		2.9
Varity_R		0.15
gMVP		0.12

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-228563937;