14-22813250-A-T
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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
NM_003982.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 9.32
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 |
---|---|---|---|---|---|---|---|---|
SLC7A7 | NM_003982.4 | c.149T>A | p.Met50Lys | missense_variant | 2/10 | ENST00000674313.1 | NP_003973.3 | |
SLC7A7 | NM_001126105.3 | c.149T>A | p.Met50Lys | missense_variant | 3/11 | NP_001119577.1 | ||
SLC7A7 | NM_001126106.4 | c.149T>A | p.Met50Lys | missense_variant | 3/11 | NP_001119578.1 | ||
SLC7A7 | XM_011537299.2 | c.149T>A | p.Met50Lys | missense_variant | 2/10 | XP_011535601.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC7A7 | ENST00000674313.1 | c.149T>A | p.Met50Lys | missense_variant | 2/10 | NM_003982.4 | ENSP00000501493.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461546Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727014
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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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 submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2022 | Variant 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 provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;.;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;.;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;.;.;.;.;.;.
Polyphen
D;D;D;D;D;.;.;.;.;.;.
Vest4
MutPred
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
MPC
0.93
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at