rs147458082

chr5-1201691-G-Achr5-1201691-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001003841.3(SLC6A19):c.41G>A(p.Arg14Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00126 in 1,610,690 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: SLC6A19 NM_001003841.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.42

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055764914).
• BP6: Variant 5-1201691-G-A is Benign according to our data. Variant chr5-1201691-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00181 (275/152314) while in subpopulation EAS AF= 0.039 (202/5180). AF 95% confidence interval is 0.0346. There are 7 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A19	NM_001003841.3	c.41G>A	p.Arg14Gln	missense_variant	1/12	ENST00000304460.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A19	ENST00000304460.11	c.41G>A	p.Arg14Gln	missense_variant	1/12	1	NM_001003841.3	P1
SLC6A19	ENST00000515652.5	c.41G>A	p.Arg14Gln	missense_variant, NMD_transcript_variant	1/11	2

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152196 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0387

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00358 AC: 880 AN: 245624 Hom.: 19 AF XY: 0.00334 AC XY: 447 AN XY: 133910

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0374

Gnomad SAS exome AF: 0.00504

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00121 AC: 1761 AN: 1458376 Hom.: 25 Cov.: 31 AF XY: 0.00130 AC XY: 942 AN XY: 725654

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0281

Gnomad4 SAS exome AF: 0.00476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152314 Hom.: 7 Cov.: 34 AF XY: 0.00215 AC XY: 160 AN XY: 74476

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0390

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00143 Hom.: 5

Bravo AF: 0.00208

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00371 AC: 449

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.36
Sift	Benign	0.38	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.42
MVP		0.84
MPC		0.80
ClinPred		0.031	T
GERP RS		4.0
Varity_R		0.22
gMVP		0.65

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: rs147458082; hg19: chr5-1201806; COSMIC: COSV58675442;