2-44312607-C-T

Position:

chr2-44312607-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The ENST00000260649.11(SLC3A1):c.1354C>T(p.Arg452Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000867 in 1,613,856 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R452Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

SLC3A1
ENST00000260649.11 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.98

Variant links:

Genes affected

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SLC3A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 2-44312607-C-T is Pathogenic according to our data. Variant chr2-44312607-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 336205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4 linkuse as main transcript	c.1354C>T	p.Arg452Trp	missense_variant	8/10	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4 linkuse as main transcript	c.1354C>T	p.Arg452Trp	missense_variant	8/10		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11 linkuse as main transcript	c.1354C>T	p.Arg452Trp	missense_variant	8/10	1	NM_000341.4	ENSP00000260649	P1	Q07837-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000103

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251238

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1461612

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74454

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:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 24, 2023	Criteria applied: PS4,PM5,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2022	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 336205). This missense change has been observed in individual(s) with cystinuria (PMID: 9186880, 25296721, 30146843; Invitae). This variant is present in population databases (rs201502095, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 452 of the SLC3A1 protein (p.Arg452Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SLC3A1 c.1354C>T (p.Arg452Trp) variant has been reported in eight studies in which it is found in at least ten individuals with cystinuria, including three homozygotes, four compound heterozygotes, two heterozygotes in whom a second variant was not identified, and one heterozygote who carried a second heterozygous variant in the SLC7A9 gene (Endsley et al. 1997; Bisceglia et al. 2001; Guillen et al. 2004; Font-Llitjos et al. 2005; Skopkova et al. 2005; Brauers et al. 2006; Eggerman et al. 2011; Halbritter et al. 2012). The variant was absent from a total of 178 controls, but is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg452Trp variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;D;.;.;.;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.3

.;H;.;H;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.6

.;D;D;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;.;.;.;.;.

Vest4

0.99

MVP

0.99

MPC

0.034

ClinPred

0.99

GERP RS

4.0

Varity_R

0.91

gMVP

0.99

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

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