chr19-32864206-G-A

Position:

chr19-32864206-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The ENST00000023064.9(SLC7A9):c.368C>T(p.Thr123Met) variant causes a missense change. The variant allele was found at a frequency of 0.000236 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T123T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SLC7A9
ENST00000023064.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:4

Conservation

PhyloP100: 5.44

Variant links:

Genes affected

SLC7A9 (HGNC:11067): (solute carrier family 7 member 9) This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. Alternate transcript variants, which encode the same protein, have been found for this gene. [provided by RefSeq, Jul 2011]

SLC7A9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a helix (size 17) in uniprot entity BAT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000023064.9

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-32864206-G-A is Pathogenic according to our data. Variant chr19-32864206-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5793.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=4, Uncertain_significance=2}. Variant chr19-32864206-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A9	NM_014270.5 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	4/13	ENST00000023064.9	NP_055085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A9	ENST00000023064.9 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	4/13	1	NM_014270.5	ENSP00000023064	P1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251344

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000281

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000217

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:7Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 30, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 strong, PP1 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2023	Variant summary: SLC7A9 c.368C>T (p.Thr123Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251344 control chromosomes (gnomAD). c.368C>T has been reported in the literature in multiple individuals affected with Cystinuria, including at least four individuals with a biallelic genotype (e.g. Font_2001, Skopkov_2005, Wong_2015, Gaildrat_2017, Alghamdi_2020, Domingo-Gallego_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 33262960, 33532864, 11157794, 28717662, 16138908, 25109415). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either pathogenic (n=3)/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2018	The SLC7A9 c.368C>T (p.Thr123Met) variant has been reported in at least six studies and is found in a total of ten individuals including one in a homozygous state, five in a compound heterozygous state including one sibling pair, and four in a heterozygous state. (Font et al. 2001; Font-Llitjos et al. 2005; Skopkova et al. 2005; Eggermann et al. 2007; Bisceglia et al. 2010). All individuals presented with type I or non-type I phenotypes, and this variant is suggested to be associated with a mild form of the disease (Font et al. 2001). The p.Thr123Met variant was absent from 100 control chromosomes, but is reported at a frequency of 0.000378 in the Latino population of the Genome Aggregation Database. This variant is located in a transmembrane domain of the SLC7A9 protein (Font et al. 2001). Structurally, the p.Thr123Met variant is predicted to alter the hydrogen bond between the Thr123 and Thr121 residue (Martell et al. 2017). While cystinuria generally displays an autosomal recessive mode of inheritance, some heterozygous carriers of variants in the SLC7A9 gene have abnormal urinary amino acid patterns and an increased risk of kidney stones (Eggermann et al. 2012). Based on the collective evidence, the p.Thr123Met variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2024	Observed in apparent homozygous state in patients with cystinuria in the literature and not observed in homozygous state in controls (PMID: 16138908, 33262960); Observed with a second SLC7A9 variant in individuals with cystinuria in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in most cases (PMID: 17539912, 19782624, 28717662, 33349102, 33532864, 25964309); Associated with a range of amino acid excretion patterns, from nearly normal to hyperexcretion of cystine, in individuals harboring this variant in the heterozygous state (PMID: 22480232, 15635077); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28717662, 28812535, 28270646, 25109415, 20981092, 11157794, 26990548, 6031738, 12234283, 12036192, 22480232, 15635077, 19782624, 31589614, 33532864, 14991253, 16834950, 33262960, 25964309, 33349102, 16138908, 17539912) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2021	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the SLC7A9 protein (p.Thr123Met). This variant is present in population databases (rs79987078, gnomAD 0.04%). This missense change has been observed in individual(s) with non-type 1 cystinuria (PMID: 16138908, 19782624, 25964309, 28717662). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5793). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.9e-12

A;A;A

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.031

.;D;.

Sift4G

Uncertain

0.031

D;D;D

Polyphen

0.018

B;B;B

Vest4

0.39

MVP

0.86

MPC

0.84

ClinPred

0.13

GERP RS

4.0

Varity_R

0.46

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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