rs121908676

Positions:

• chr14-22813398-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003982.4(SLC7A7):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC7A7 NM_003982.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.33

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-22813398-T-G is Pathogenic according to our data. Variant chr14-22813398-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 6208.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22813398-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A7	NM_003982.4	c.1A>C	p.Met1?	initiator_codon_variant	2/10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3	c.1A>C	p.Met1?	initiator_codon_variant	3/11		NP_001119577.1
SLC7A7	NM_001126106.4	c.1A>C	p.Met1?	initiator_codon_variant	3/11		NP_001119578.1
SLC7A7	XM_011537299.2	c.1A>C	p.Met1?	initiator_codon_variant	2/10		XP_011535601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1	c.1A>C	p.Met1?	initiator_codon_variant	2/10		NM_003982.4	ENSP00000501493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lysinuric protein intolerance Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 05, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SLC7A7 protein in which other variant(s) (p.Glu36del) have been observed in individuals with SLC7A7-related conditions (PMID: 15756301). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that disruption of the initiator codon affects SLC7A7 function (PMID: 15776427, 17764084). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 6208). Disruption of the initiator codon has been observed in individual(s) with SLC7A7-related conditions. (PMID: 10631139). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SLC7A7 mRNA. The next in-frame methionine is located at codon 50. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Benign	0.71
DEOGEN2	Benign	0.14	T;T;T;T;T;T;.;T;.;T;T;.;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;.;.;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;N;N;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.074	T;T;T;T;T;T;T;T;T;T;T;D;.
Sift4G	Benign	0.32	T;T;T;T;T;.;.;.;.;.;.;D;.
Polyphen		0.13	B;B;B;B;B;.;.;.;.;.;.;.;.
Vest4		0.69
MutPred		0.99		Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);Loss of phosphorylation at S4 (P = 0.1944);
MVP		0.55
ClinPred		0.68	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.42

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: rs121908676; hg19: chr14-23282607;