14-22813250-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003982.4(SLC7A7):​c.149T>A​(p.Met50Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,738 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC7A7
NM_003982.4 missense

Scores

14
4
1

Clinical Significance

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

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
SLC7A7 (HGNC:11065): (solute carrier family 7 member 7) The protein encoded by this gene is the light subunit of a cationic amino acid transporter. This sodium-independent transporter is formed when the light subunit encoded by this gene dimerizes with the heavy subunit transporter protein SLC3A2. This transporter is found in epithelial cell membranes where it transfers cationic and large neutral amino acids from the cell to the extracellular space. Defects in this gene are a cause of lysinuric protein intolerance (LPI). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 14-22813250-A-T is Pathogenic according to our data. Variant chr14-22813250-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22813250-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC7A7NM_003982.4 linkuse as main transcriptc.149T>A p.Met50Lys missense_variant 2/10 ENST00000674313.1 NP_003973.3
SLC7A7NM_001126105.3 linkuse as main transcriptc.149T>A p.Met50Lys missense_variant 3/11 NP_001119577.1 Q9UM01A0A0S2Z502
SLC7A7NM_001126106.4 linkuse as main transcriptc.149T>A p.Met50Lys missense_variant 3/11 NP_001119578.1 Q9UM01A0A0S2Z502
SLC7A7XM_011537299.2 linkuse as main transcriptc.149T>A p.Met50Lys missense_variant 2/10 XP_011535601.1 Q9UM01A0A0S2Z502

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC7A7ENST00000674313.1 linkuse as main transcriptc.149T>A p.Met50Lys missense_variant 2/10 NM_003982.4 ENSP00000501493.1 Q9UM01

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461546
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lysinuric protein intolerance Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 31, 2022Variant summary: SLC7A7 c.149T>A (p.Met50Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251180 control chromosomes (gnomAD). The variant, c.149T>A, has been reported in the literature in at least one patient affected with Lysinuric Protein Intolerance as a paternally inherited variant, where the variant in trans was not identified (Palacin_2001, Sperandeo_2005, Sperandeo_2008, Barilli_2010, Barilli_2012). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant abolished the transport activities (Sperandeo_2005), in addition, transport defects and other functional disturbances were also demonstrated in patient derived cells (Barilli_2010, Barilli_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;D;D;D;D;D;.;D;.;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;.;.;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.9
H;H;H;H;H;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-4.1
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;.;.;.;.;.
Polyphen
1.0
D;D;D;D;D;.;.;.;.;.;.
Vest4
0.99
MutPred
0.90
Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);Gain of ubiquitination at M50 (P = 0.0211);
MVP
0.76
MPC
0.93
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.98
gMVP
0.95

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.

Other links and lift over

dbSNP: rs386833811; hg19: chr14-23282459; API