2-227685582-T-G

Variant names:

• chr2-227685582-T-G
• rs34020562
• NM_025243.4:c.*1815A>C

Variant summary

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

The NM_025243.4(SLC19A3):​c.*1815A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 151,982 control chromosomes in the GnomAD database, including 11,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11628 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: SLC19A3 NM_025243.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.214
• 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=-0.89).
• BP6: Variant 2-227685582-T-G is Benign according to our data. Variant chr2-227685582-T-G is described in ClinVar as [Benign]. Clinvar id is 334844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A3	NM_025243.4	c.*1815A>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000644224.2	NP_079519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2	c.*1815A>C		3_prime_UTR_variant	Exon 6 of 6		NM_025243.4	ENSP00000495385.1
SLC19A3	ENST00000647113.1	n.*2294A>C		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000494966.1
SLC19A3	ENST00000647113.1	n.*2294A>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000494966.1
SLC19A3	ENST00000676066.1	n.*98A>C		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57201 AN: 151856 Hom.: 11620 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.377 AC: 57231 AN: 151974 Hom.: 11628 Cov.: 32 AF XY: 0.373 AC XY: 27671 AN XY: 74258

African (AFR) AF: 0.310 AC: 12842 AN: 41456

American (AMR) AF: 0.303 AC: 4623 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3468

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5166

South Asian (SAS) AF: 0.250 AC: 1200 AN: 4808

European-Finnish (FIN) AF: 0.443 AC: 4677 AN: 10546

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31249 AN: 67952

Other (OTH) AF: 0.374 AC: 789 AN: 2108

Alfa AF: 0.269 Hom.: 679

Bravo AF: 0.360

Asia WGS AF: 0.126 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Thiamine Metabolism Dysfunction Syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.89
CADD	Benign	2.3
DANN	Benign	0.67
PhyloP100		0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34020562; hg19: chr2-228550298;