chr2-227710291-C-T

Variant names:

• chr2-227710291-C-T
• rs13007334
• NM_025243.4:c.-3+7652G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025243.4(SLC19A3):​c.-3+7652G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 152,014 control chromosomes in the GnomAD database, including 15,183 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (15183 hom., cov: 32)
• Consequence: SLC19A3 NM_025243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.543 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	NM_025243.4	MANE Select	c.-3+7652G>A		intron	N/A	NP_079519.1
	SLC19A3	NM_001371411.1		c.-3+4158G>A		intron	N/A	NP_001358340.1
	SLC19A3	NM_001371413.1		c.-211+7652G>A		intron	N/A	NP_001358342.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	ENST00000644224.2	MANE Select	c.-3+7652G>A		intron	N/A	ENSP00000495385.1
	SLC19A3	ENST00000258403.8	TSL:1	c.-3+4158G>A		intron	N/A	ENSP00000258403.3
	SLC19A3	ENST00000425817.6	TSL:1	n.-102-7600G>A		intron	N/A	ENSP00000397393.2

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63747 AN: 151896 Hom.: 15188 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.485

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.419 AC: 63739 AN: 152014 Hom.: 15183 Cov.: 32 AF XY: 0.412 AC XY: 30593 AN XY: 74292

African (AFR) AF: 0.227 AC: 9398 AN: 41464

American (AMR) AF: 0.425 AC: 6487 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1919 AN: 3470

East Asian (EAS) AF: 0.114 AC: 590 AN: 5168

South Asian (SAS) AF: 0.349 AC: 1681 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4700 AN: 10538

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.547 AC: 37207 AN: 67964

Other (OTH) AF: 0.480 AC: 1014 AN: 2114

Alfa AF: 0.505 Hom.: 9678

Bravo AF: 0.410

Asia WGS AF: 0.236 AC: 824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
DANN	Benign	0.73
PhyloP100		0.28
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: rs13007334; hg19: chr2-228575007;