rs121908676

Variant names:

• chr14-22813398-T-C
• NM_003982.4:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-22813398-T-C
• chr14-22813398-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PS1_Moderate PM2 PP5_Very_Strong

The NM_003982.4(SLC7A7):​c.1A>G​(p.Met1?) variant causes a start lost 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC7A7 NM_003982.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 50 codons. Genomic position: 22813251. Lost 0.096 part of the original CDS.
• PS1: Another start lost variant in NM_003982.4 (SLC7A7) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-22813398-T-C is Pathogenic according to our data. Variant chr14-22813398-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2155518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A7	NM_003982.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3	c.1A>G	p.Met1?	start_lost	Exon 3 of 11		NP_001119577.1
SLC7A7	NM_001126106.4	c.1A>G	p.Met1?	start_lost	Exon 3 of 11		NP_001119578.1
SLC7A7	XM_011537299.2	c.1A>G	p.Met1?	start_lost	Exon 2 of 10		XP_011535601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 10		NM_003982.4	ENSP00000501493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysinuric protein intolerance Pathogenic:2

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SLC7A7 mRNA. The next in-frame methionine is located at codon 50. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with lysinuric protein intolerance (PMID: 10631139). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2155518). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Benign	0.64
DEOGEN2	Benign	0.14	T;T;T;T;T;T;.;T;.;T;T;.;.
Eigen	Benign	0.038
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;.;.;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N;N;N;N;N;N;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.026	D;D;D;D;D;.;.;.;.;.;.;D;.
Polyphen		0.43	B;B;B;B;B;.;.;.;.;.;.;.;.
Vest4		0.73
MutPred		0.99		Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);Loss of glycosylation at T5 (P = 0.2477);
MVP		0.61
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23282607;