rs11568438

Positions:

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

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]

SLC7A7 links:

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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
SLC7A7	NM_003982.4 linkuse as main transcript	c.272C>T	p.Ala91Val	missense_variant	2/10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3 linkuse as main transcript	c.272C>T	p.Ala91Val	missense_variant	3/11		NP_001119577.1	Q9UM01A0A0S2Z502
SLC7A7	NM_001126106.4 linkuse as main transcript	c.272C>T	p.Ala91Val	missense_variant	3/11		NP_001119578.1	Q9UM01A0A0S2Z502
SLC7A7	XM_011537299.2 linkuse as main transcript	c.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
SLC7A7	ENST00000674313.1 linkuse as main transcript	c.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.:

Cov.:

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.:

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.:

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.:

Cov.:

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.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0201

AC:

173

ExAC

AF:

0.0123

AC:

1487

Asia WGS

AF:

0.00115

AC:

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 provided	phenotyping only	GenomeConnect, 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 submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC7A7: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lysinuric protein intolerance

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2021	Variant 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 submitter	clinical testing	GeneDx	Dec 07, 2016	This 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 submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

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

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

MutationAssessor

Uncertain

2.9

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

PrimateAI

Pathogenic

0.79

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over