5-1216947-T-G
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001003841.3(SLC6A19):c.1173+2T>G variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000267 in 1,612,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 35)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
SLC6A19
NM_001003841.3 splice_donor, intron
NM_001003841.3 splice_donor, intron
Scores
2
2
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.46
Genes affected
SLC6A19 (HGNC:27960): (solute carrier family 6 member 19) This gene encodes a system B(0) transmembrane protein that actively transports most neutral amino acids across the apical membrane of epithelial cells. Mutations in this gene may result in Hartnup disorder, an inherited disease with symptoms such as pellagra, cerebellar ataxia, and psychosis. The expression and function of B0AT1 (SLC6A19) in intestinal cells depends on the presence of the accessory protein angiotensin-converting enzyme 2 (ACE2) which, among other functions, acts as a chaperone for membrane trafficking of B0AT1. The ACE2 is also the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and for SARS-CoV-2 that is causing the coronavirus 2019 (COVID-19) pandemic [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-1216947-T-G is Pathogenic according to our data. Variant chr5-1216947-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 449553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1216947-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC6A19 | ENST00000304460.11 | c.1173+2T>G | splice_donor_variant, intron_variant | 1 | NM_001003841.3 | ENSP00000305302.10 | ||||
| SLC6A19 | ENST00000515652.5 | n.*118+2T>G | splice_donor_variant, intron_variant | 2 | ENSP00000425701.1 |
Frequencies
GnomAD3 genomes 0.000237 AC: 36AN: 152218Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.000296 AC: 74AN: 249668Hom.: 0 AF XY: 0.000303 AC XY: 41AN XY: 135256
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GnomAD4 exome AF: 0.000271 AC: 395AN: 1460188Hom.: 0 Cov.: 36 AF XY: 0.000270 AC XY: 196AN XY: 726400
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GnomAD4 genome 0.000237 AC: 36AN: 152218Hom.: 0 Cov.: 35 AF XY: 0.000323 AC XY: 24AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This sequence change affects a donor splice site in intron 8 of the SLC6A19 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC6A19 are known to be pathogenic (PMID: 15286787, 15286788). This variant is present in population databases (rs142979576, gnomAD 0.07%). Disruption of this splice site has been observed in individuals with Hartnup disorder (PMID: 15286787, 15286788). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449553). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2024 | Observed in siblings with features of Hartnup disorder who also possessed a second SLC6A19 variant (PMID: 15286788); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Also known as IVS8+2T>G; This variant is associated with the following publications: (PMID: 25525159, 25082825, 31589614, 31908951, 15286788, 33144682, 15286787) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 06, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Neutral 1 amino acid transport defect Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2023 | Variant summary: SLC6A19 c.1173+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0003 in 249668 control chromosomes. This frequency does not allow conclusions about variant significance. c.1173+2T>G has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Hartnup Disease (example, Kleta_2004, Azamov_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
SLC6A19-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2024 | The SLC6A19 c.1173+2T>G variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with Hartnup disorder (Table 1, Seow et al. 2004. PubMed ID: 15286788; Kleta et al. 2004. PubMed ID: 15286787). This variant is reported in 0.068% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1217062-T-G). Variants that disrupt the consensus splice donor site in SLC6A19 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at