chr14-22773982-G-C

Position:

chr14-22773982-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003982.4(SLC7A7):c.1380C>G(p.Ile460Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,614,170 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 5 hom. )

Consequence

SLC7A7
NM_003982.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 1.21

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:

SLC7A7 (HGNC:):

SLC7A7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062741637).

BP6

Variant 14-22773982-G-C is Benign according to our data. Variant chr14-22773982-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 312812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22773982-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A7	NM_003982.4 linkuse as main transcript	c.1380C>G	p.Ile460Met	missense_variant	9/10	ENST00000674313.1	NP_003973.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1 linkuse as main transcript	c.1380C>G	p.Ile460Met	missense_variant	9/10		NM_003982.4	ENSP00000501493.1		Q9UM01

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

356

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00319

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00233

AC:

587

AN:

251450

Hom.:

AF XY:

0.00232

AC XY:

315

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00391

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00280

AC:

4090

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1972

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.00331

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152318

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00317

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00253

AC:

307

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysinuric protein intolerance

Uncertain:1Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 14, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	SLC7A7: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 01, 2023

Variant summary: SLC7A7 c.1380C>G (p.Ile460Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251450 control chromosomes. The observed variant frequency is approximately two 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, c.1380C>G has not been reported in the literature in individuals affected with Lysinuric Protein Intolerance and no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation classifying the variant as likely benign (n=4) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

SLC7A7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.12

T;T;T;T;T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.83

.;.;.;.;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0063

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

0.020

N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.24

T;T;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T;T

Polyphen

0.070

B;B;B;B;B;.

Vest4

0.37

MVP

0.49

MPC

0.22

ClinPred

0.0069

GERP RS

3.2

Varity_R

0.050

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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