rs567478582

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000341.4(SLC3A1):c.1094G>A(p.Arg365Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,054 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. R365P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

SLC3A1
NM_000341.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.53

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

cystinuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
cystinuria type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC3A1 links:

ENSG00000285542 (HGNC:):

ENSG00000285542 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000341.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-44301085-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3586650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -3.1434 (below the threshold of 3.09). Trascript score misZ: -3.2509 (below the threshold of 3.09). GenCC associations: The gene is linked to cystinuria type A, cystinuria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 2-44301085-G-A is Pathogenic according to our data. Variant chr2-44301085-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 562304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC3A1	NM_000341.4 link	c.1094G>A	p.Arg365Gln	missense_variant	Exon 6 of 10	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4 link	c.1094G>A	p.Arg365Gln	missense_variant	Exon 6 of 10		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC3A1	ENST00000260649.11 link	c.1094G>A	p.Arg365Gln	missense_variant	Exon 6 of 10	1	NM_000341.4	ENSP00000260649.6
ENSG00000285542	ENST00000649044.1 link	n.*1105G>A		non_coding_transcript_exon_variant	Exon 11 of 15			ENSP00000497083.1
ENSG00000285542	ENST00000649044.1 link	n.*1105G>A		3_prime_UTR_variant	Exon 11 of 15			ENSP00000497083.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251376

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41484

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000556

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:2

Sep 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg365 amino acid residue in SLC3A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12234283, 14561219, 18332091, 25964309). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 562304). This missense change has been observed in individual(s) with cystinuria (PMID: 14991253, 25109415, 33349102; Invitae). This variant is present in population databases (rs567478582, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the SLC3A1 protein (p.Arg365Gln). -

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;D;D;.;.;.;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

.;M;.;M;M;M;.;.

PhyloP100

7.5

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.90

Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);.;.;

MVP

1.0

MPC

0.032

ClinPred

0.91

GERP RS

5.3

Varity_R

0.86

gMVP

0.92

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over