rs386833812

chr14-22813180-CAGAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003982.4(SLC7A7):c.215_218del(p.Ser72TrpfsTer97) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S72S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC7A7 NM_003982.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-22813180-CAGAG-C is Pathogenic according to our data. Variant chr14-22813180-CAGAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 56364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22813180-CAGAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A7	NM_003982.4	c.215_218del	p.Ser72TrpfsTer97	frameshift_variant	2/10	ENST00000674313.1
SLC7A7	NM_001126105.3	c.215_218del	p.Ser72TrpfsTer97	frameshift_variant	3/11
SLC7A7	NM_001126106.4	c.215_218del	p.Ser72TrpfsTer97	frameshift_variant	3/11
SLC7A7	XM_011537299.2	c.215_218del	p.Ser72TrpfsTer97	frameshift_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A7	ENST00000674313.1	c.215_218del	p.Ser72TrpfsTer97	frameshift_variant	2/10		NM_003982.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysinuric protein intolerance Pathogenic:3

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 13, 2023	For these reasons, this variant has been classified as Pathogenic. This variant is also known as 455delCTCT. This premature translational stop signal has been observed in individual(s) with lysinuric protein intolerance (PMID: 10631139). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser72Trpfs*97) in the SLC7A7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC7A7 are known to be pathogenic (PMID: 10631139, 17764084). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 10, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs386833812; hg19: chr14-23282389;