5-1216947-T-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_001003841.3(SLC6A19):c.1173+2T>G variant causes a splice donor 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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.46

Variant links:

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]

SLC6A19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Splicing 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;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A19	NM_001003841.3 linkuse as main transcript	c.1173+2T>G		splice_donor_variant		ENST00000304460.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A19	ENST00000304460.11 linkuse as main transcript	c.1173+2T>G		splice_donor_variant		1	NM_001003841.3	P1
SLC6A19	ENST00000515652.5 linkuse as main transcript	c.*118+2T>G		splice_donor_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000296

AC:

AN:

249668

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

135256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.000535

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000271

AC:

395

AN:

1460188

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

726400

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000760

Gnomad4 NFE exome

AF:

0.000305

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000237

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 15286788, 25082825, 15286787, 31589614, 33144682) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, 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:3

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -

SLC6A19-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

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. -

Neutral 1 amino acid transport defect;C0268654:Iminoglycinuria;C0543541:Hyperglycinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Benign

-0.18

Cadd

Uncertain

Dann

Benign

0.93

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

GERP RS

3.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 2

DS_DL_spliceai

0.98

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over