rs11568438

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A91E) has been classified as Uncertain significance.

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

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

lysinuric protein intolerance
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

SLC7A7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A7	NM_003982.4 link	c.272C>T	p.Ala91Val	missense_variant	Exon 2 of 10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3 link	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 11		NP_001119577.1	Q9UM01A0A0S2Z502
SLC7A7	NM_001126106.4 link	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 11		NP_001119578.1	Q9UM01A0A0S2Z502
SLC7A7	XM_011537299.2 link	c.272C>T	p.Ala91Val	missense_variant	Exon 2 of 10		XP_011535601.1	Q9UM01A0A0S2Z502

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1 link	c.272C>T	p.Ala91Val	missense_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.0125

AC:

3138

AN:

251372

AF XY:

0.0122

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 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

African (AFR)

AF:

0.00239

AC:

AN:

33480

American (AMR)

AF:

0.00599

AC:

268

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00888

AC:

232

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000614

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0247

AC:

1318

AN:

53418

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0189

AC:

21009

AN:

1112012

Other (OTH)

AF:

0.0147

AC:

889

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1524

3048

4572

6096

7620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0128

AC:

1949

AN:

152212

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

901

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41528

American (AMR)

AF:

0.00727

AC:

111

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0210

AC:

223

AN:

10604

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0211

AC:

1437

AN:

68006

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

193

290

386

483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0176

Hom.:

138

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC7A7: BS1, BS2 -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Lysinuric protein intolerance

Benign:4

Nov 27, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:2

Dec 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Autoinflammatory syndrome

Benign:1

Apr 19, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.;.;.;.

PhyloP100

6.9

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

Mutation Taster

=37/63

disease causing

(source)

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

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rs11568438

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over