rs11568438

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003982.4(SLC7A7):​c.272C>T​(p.Ala91Val) variant causes a missense change. The variant allele was found at a frequency of 0.016 in 1,614,104 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 31)
Exomes 𝑓: 0.016 ( 242 hom. )

Consequence

SLC7A7
NM_003982.4 missense

Scores

7
8
3

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 6.88
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.014431596).
BP6
Variant 14-22813127-G-A is Benign according to our data. Variant chr14-22813127-G-A is described in ClinVar as [Benign]. Clinvar id is 380186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22813127-G-A is described in Lovd as [Likely_benign]. Variant chr14-22813127-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1949/152212) while in subpopulation NFE AF= 0.0211 (1437/68006). AF 95% confidence interval is 0.0202. There are 19 homozygotes in gnomad4. There are 901 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC7A7NM_003982.4 linkuse as main transcriptc.272C>T p.Ala91Val missense_variant 2/10 ENST00000674313.1 NP_003973.3
SLC7A7NM_001126105.3 linkuse as main transcriptc.272C>T p.Ala91Val missense_variant 3/11 NP_001119577.1 Q9UM01A0A0S2Z502
SLC7A7NM_001126106.4 linkuse as main transcriptc.272C>T p.Ala91Val missense_variant 3/11 NP_001119578.1 Q9UM01A0A0S2Z502
SLC7A7XM_011537299.2 linkuse as main transcriptc.272C>T p.Ala91Val 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.272C>T p.Ala91Val missense_variant 2/10 NM_003982.4 ENSP00000501493.1 Q9UM01

Frequencies

GnomAD3 genomes
AF:
0.0128
AC:
1950
AN:
152096
Hom.:
19
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00302
Gnomad AMI
AF:
0.0208
Gnomad AMR
AF:
0.00734
Gnomad ASJ
AF:
0.00403
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0210
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0211
Gnomad OTH
AF:
0.00909
GnomAD3 exomes
AF:
0.0125
AC:
3138
AN:
251372
Hom.:
28
AF XY:
0.0122
AC XY:
1652
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00277
Gnomad AMR exome
AF:
0.00512
Gnomad ASJ exome
AF:
0.0101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.0246
Gnomad NFE exome
AF:
0.0193
Gnomad OTH exome
AF:
0.0134
GnomAD4 exome
AF:
0.0163
AC:
23868
AN:
1461892
Hom.:
242
Cov.:
71
AF XY:
0.0160
AC XY:
11618
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00239
Gnomad4 AMR exome
AF:
0.00599
Gnomad4 ASJ exome
AF:
0.00888
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000614
Gnomad4 FIN exome
AF:
0.0247
Gnomad4 NFE exome
AF:
0.0189
Gnomad4 OTH exome
AF:
0.0147
GnomAD4 genome
AF:
0.0128
AC:
1949
AN:
152212
Hom.:
19
Cov.:
31
AF XY:
0.0121
AC XY:
901
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.00301
Gnomad4 AMR
AF:
0.00727
Gnomad4 ASJ
AF:
0.00403
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0210
Gnomad4 NFE
AF:
0.0211
Gnomad4 OTH
AF:
0.00900
Alfa
AF:
0.0175
Hom.:
74
Bravo
AF:
0.0119
TwinsUK
AF:
0.0154
AC:
57
ALSPAC
AF:
0.0182
AC:
70
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.0201
AC:
173
ExAC
AF:
0.0123
AC:
1487
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0184
EpiControl
AF:
0.0161

ClinVar

Significance: Benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024SLC7A7: BS1, BS2 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Lysinuric protein intolerance Benign:4
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Nov 27, 2019- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 03, 2021Variant summary: SLC7A7 c.272C>T (p.Ala91Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 251372 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC7A7 causing Lysinuric Protein Intolerance phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.272C>T in individuals affected with Lysinuric Protein Intolerance and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingGeneDxDec 07, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Autoinflammatory syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 19, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;D;D;D;D;.;D;.;D;D
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;.;.;.;D;D;D;D;D;D;D
MetaRNN
Benign
0.014
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.9
M;M;M;M;M;.;.;.;.;.;.
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.020
D;D;D;D;D;.;.;.;.;.;.
Polyphen
0.99
D;D;D;D;D;.;.;.;.;.;.
Vest4
0.15
MPC
0.65
ClinPred
0.011
T
GERP RS
5.4
Varity_R
0.54
gMVP
0.89

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: rs11568438; hg19: chr14-23282336; COSMIC: COSV53539800; COSMIC: COSV53539800; API