2-44312754-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_000341.4(SLC3A1):​c.1500+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000287 in 1,604,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SLC3A1
NM_000341.4 splice_donor, intron

Scores

2
5
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.33
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08163265 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP5
Variant 2-44312754-G-T is Pathogenic according to our data. Variant chr2-44312754-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 284275.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
SLC3A1NM_000341.4 linkc.1500+1G>T splice_donor_variant, intron_variant Intron 8 of 9 ENST00000260649.11 NP_000332.2 Q07837-1A0A0S2Z4E1
SLC3A1XM_011533047.4 linkc.1500+1G>T splice_donor_variant, intron_variant Intron 8 of 9 XP_011531349.1 B8ZZK1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC3A1ENST00000260649.11 linkc.1500+1G>T splice_donor_variant, intron_variant Intron 8 of 9 1 NM_000341.4 ENSP00000260649.6 Q07837-1
ENSG00000285542ENST00000649044.1 linkn.*1511+1G>T splice_donor_variant, intron_variant Intron 13 of 14 ENSP00000497083.1 A0A3B3IS24

Frequencies

GnomAD3 genomes
AF:
0.0000270
AC:
4
AN:
148158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000661
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249462
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
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:
0.0000443
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000288
AC:
42
AN:
1456836
Hom.:
0
Cov.:
30
AF XY:
0.0000331
AC XY:
24
AN XY:
724978
show subpopulations
Gnomad4 AFR exome
AF:
0.0000320
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000351
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000270
AC:
4
AN:
148158
Hom.:
0
Cov.:
32
AF XY:
0.0000276
AC XY:
2
AN XY:
72456
show subpopulations
Gnomad4 AFR
AF:
0.0000266
Gnomad4 AMR
AF:
0.0000661
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000340
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystinuria Pathogenic:3
Mar 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the SLC3A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). This variant is present in population databases (no rsID available, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with cystinuria (PMID: 8731106, 28646536). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 26, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 26, 2022
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1, PM2, PM3_Strong -

not provided Pathogenic:2
Jun 22, 2022
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

DNA sequence analysis of the SLC3A1 gene demonstrated a sequence change in the canonical splice donor site of intron 8, c.1500+1G>T. This sequence change has been described in the gnomAD database with a frequency of 0.0044% in the non-Finnish European subpopulation (dbSNP rs886042834). This sequence change has previously been described in multiple individuals with SLC3A1-related cystinuria in the homozygous and compound heterozygous states (PMID: 28049243, 28646536, 28717662, 11748844, 8731106, 11260385). This sequence change is predicted to affect normal splicing of the SLC3A1 gene and result in an abnormal protein, however functional studies have not been performed to prove this conclusively. Based on these collective evidences, this sequence change is classified as pathogenic. -

Jun 15, 2018
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Mar 13, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1500+1G>T intronic alteration consists of a G to T substitution one nucleotide after coding exon 8 of the SLC3A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/249462) total alleles studied. The highest observed frequency was 0.004% (5/112884) of European (non-Finnish) alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC3A1, in multiple individuals with SLC3A1-related cystinuria and co-segregates with disease in several families (Harnevik, 2001; Tostivint, 2017; Gaildrat, 2017; Horsford, 1996). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Uncertain
0.15
D
ClinPred
0.65
D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.63
Position offset: 44
DS_DL_spliceai
0.99
Position offset: -1

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.

Other links and lift over

dbSNP: rs886042834; hg19: chr2-44539893; API