2-227696084-GAA-GA

Variant names:

• chr2-227696084-GA-G
• rs11334205
• NM_025243.4:c.980-4delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_025243.4(SLC19A3):​c.980-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene SLC19A3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.95 (68683 hom., cov: 0)
  • Exomes 𝑓: 0.99 (723316 hom.)
• Consequence: SLC19A3 NM_025243.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0760
• Publications: 10 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

Specifications for SLC19A3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-227696084-GA-G is Benign according to our data. Variant chr2-227696084-GA-G is described in ClinVar as Benign. ClinVar VariationId is 215155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	NM_025243.4	MANE Select	c.980-4delT		splice_region intron	N/A	NP_079519.1	Q9BZV2
	SLC19A3	NM_001371411.1		c.980-4delT		splice_region intron	N/A	NP_001358340.1	Q9BZV2
	SLC19A3	NM_001371412.1		c.980-4delT		splice_region intron	N/A	NP_001358341.1	Q9BZV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A3	ENST00000644224.2	MANE Select	c.980-4delT		splice_region intron	N/A	ENSP00000495385.1	Q9BZV2
	SLC19A3	ENST00000258403.8	TSL:1	c.980-4delT		splice_region intron	N/A	ENSP00000258403.3	Q9BZV2
	SLC19A3	ENST00000425817.6	TSL:1	n.*1005-4delT		splice_region intron	N/A	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes AF: 0.947 AC: 143939 AN: 152024 Hom.: 68660 Cov.: 0

Gnomad AFR AF: 0.816

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.964

GnomAD2 exomes AF: 0.986 AC: 247116 AN: 250528 AF XY: 0.990

Gnomad AFR exome AF: 0.810

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.995 AC: 1453354 AN: 1461204 Hom.: 723316 Cov.: 0 AF XY: 0.995 AC XY: 723698 AN XY: 726984

African (AFR) AF: 0.810 AC: 27066 AN: 33434

American (AMR) AF: 0.991 AC: 44286 AN: 44680

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26129 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39684

South Asian (SAS) AF: 1.00 AC: 86213 AN: 86246

European-Finnish (FIN) AF: 1.00 AC: 53412 AN: 53412

Middle Eastern (MID) AF: 0.993 AC: 5724 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1111285 AN: 1111484

Other (OTH) AF: 0.987 AC: 59555 AN: 60370

GnomAD4 genome AF: 0.947 AC: 144021 AN: 152142 Hom.: 68683 Cov.: 0 AF XY: 0.949 AC XY: 70610 AN XY: 74392

African (AFR) AF: 0.815 AC: 33789 AN: 41442

American (AMR) AF: 0.978 AC: 14948 AN: 15284

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10602 AN: 10602

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67978 AN: 68030

Other (OTH) AF: 0.964 AC: 2037 AN: 2114

Alfa AF: 0.977 Hom.: 13221

Bravo AF: 0.940

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Biotin-responsive basal ganglia disease (3)
-	-	2	not provided (2)
-	-	1	Thiamine Metabolism Dysfunction Syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.076
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11334205; hg19: chr2-228560800; COSMIC: COSV108048152;