chr2-227702330-T-C

Variant names:

• chr2-227702330-T-C
• rs6728344
• ENST00000419059.1:c.-12A>G

Variant summary

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

The ENST00000419059.1(SLC19A3):​c.-12A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,316 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (265 hom., cov: 32)
  • Exomes 𝑓: 0.012 (323 hom.)
• Consequence: SLC19A3 ENST00000419059.1 5_prime_UTR
• Scores: Splicing: ADA: 0.00005165
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.546
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-227702330-T-C is Benign according to our data. Variant chr2-227702330-T-C is described in ClinVar as Benign. ClinVar VariationId is 139122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A3	NM_025243.4	c.-2-10A>G		intron_variant	Intron 1 of 5	ENST00000644224.2	NP_079519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2	c.-2-10A>G		intron_variant	Intron 1 of 5		NM_025243.4	ENSP00000495385.1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5620 AN: 151766 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0327

GnomAD2 exomes AF: 0.0153 AC: 3840 AN: 251086 AF XY: 0.0133

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0122 AC: 17837 AN: 1461446 Hom.: 323 Cov.: 31 AF XY: 0.0115 AC XY: 8360 AN XY: 727042

African (AFR) AF: 0.114 AC: 3812 AN: 33440

American (AMR) AF: 0.0107 AC: 479 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00423 AC: 365 AN: 86252

European-Finnish (FIN) AF: 0.00156 AC: 83 AN: 53310

Middle Eastern (MID) AF: 0.0199 AC: 115 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11933 AN: 1111754

Other (OTH) AF: 0.0156 AC: 943 AN: 60388

GnomAD4 genome AF: 0.0371 AC: 5634 AN: 151870 Hom.: 265 Cov.: 32 AF XY: 0.0367 AC XY: 2726 AN XY: 74196

African (AFR) AF: 0.109 AC: 4508 AN: 41394

American (AMR) AF: 0.0169 AC: 258 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4812

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10514

Middle Eastern (MID) AF: 0.0313 AC: 9 AN: 288

European-Non Finnish (NFE) AF: 0.0111 AC: 758 AN: 67992

Other (OTH) AF: 0.0328 AC: 69 AN: 2104

Alfa AF: 0.0239 Hom.: 39

Bravo AF: 0.0424

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Biotin-responsive basal ganglia disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.6
DANN	Benign	0.73
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.076
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: rs6728344; hg19: chr2-228567046;