rs121908676

Variant names:

• chr14-22813398-T-C
• rs121908676
• 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. The variant received 18 ACMG points: 18P and 0B. PVS1 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• lysinuric protein intolerance

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 15 pathogenic variants. Next in-frame start position is after 50 codons. Genomic position: 22813251. Lost 0.096 part of the original CDS.
• 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 VariationId is 2155518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	NM_003982.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 2 of 10	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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	ENST00000674313.1	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 2 of 10	ENSP00000501493.1
	SLC7A7	ENST00000397528.8	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 3 of 11	ENSP00000380662.4
	SLC7A7	ENST00000397529.6	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 10	ENSP00000380663.2

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 v4.9

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
Eigen	Benign	0.038
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.31	T
PhyloP100		1.3
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.026	D
Polyphen		0.43	B
Vest4		0.73
MutPred		0.99		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
Mutation Taster		=9/191	disease causing

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

Other links and lift over

dbSNP: rs121908676; hg19: chr14-23282607;