rs11568423

chr14-22775475-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP3 BP4_Strong BP6

The NM_003982.4(SLC7A7):c.1064G>A(p.Arg355Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.014576405).
• BP6: Variant 14-22775475-C-T is Benign according to our data. Variant chr14-22775475-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312818.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A7	NM_003982.4	c.1064G>A	p.Arg355Gln	missense_variant	7/10	ENST00000674313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A7	ENST00000674313.1	c.1064G>A	p.Arg355Gln	missense_variant	7/10		NM_003982.4	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251358 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00457

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.0000889 AC: 130 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.0000935 AC XY: 68 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00244

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74430

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lysinuric protein intolerance Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 20, 2021

- -

SLC7A7-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;D;D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;D
REVEL	Pathogenic	0.76
Sift	Benign	0.051	T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.56
MVP		0.71
MPC		0.80
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.69
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs11568423; hg19: chr14-23244684;