rs121434347

chr5-1213517-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001003841.3(SLC6A19):c.718C>T(p.Arg240Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,610,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R240R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC6A19 NM_001003841.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.24

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-1213517-C-T is Pathogenic according to our data. Variant chr5-1213517-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A19	NM_001003841.3	c.718C>T	p.Arg240Ter	stop_gained	5/12	ENST00000304460.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A19	ENST00000304460.11	c.718C>T	p.Arg240Ter	stop_gained	5/12	1	NM_001003841.3	P1
SLC6A19	ENST00000515652.5	c.626C>T	p.Pro209Leu	missense_variant, NMD_transcript_variant	5/11	2

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149352 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000743

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250274 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460966 Hom.: 0 Cov.: 35 AF XY: 0.0000371 AC XY: 27 AN XY: 726814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000402 AC: 6 AN: 149352 Hom.: 0 Cov.: 24 AF XY: 0.0000275 AC XY: 2 AN XY: 72848

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000743

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutral 1 amino acid transport defect Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 17, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs121434347; hg19: chr5-1213632;