rs386833816

Positions:

• chr14-22812945-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_003982.4(SLC7A7):​c.454T>C​(p.Phe152Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F152F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.308

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-22812945-A-G is Pathogenic according to our data. Variant chr14-22812945-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56368.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-22812945-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.111234516). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A7	NM_003982.4	c.454T>C	p.Phe152Leu	missense_variant	2/10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3	c.454T>C	p.Phe152Leu	missense_variant	3/11		NP_001119577.1
SLC7A7	NM_001126106.4	c.454T>C	p.Phe152Leu	missense_variant	3/11		NP_001119578.1
SLC7A7	XM_011537299.2	c.454T>C	p.Phe152Leu	missense_variant	2/10		XP_011535601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1	c.454T>C	p.Phe152Leu	missense_variant	2/10		NM_003982.4	ENSP00000501493	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lysinuric protein intolerance Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.33	T;T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.56	.;.;.;.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.38	N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.19	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.78	T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;.
Polyphen		0.0	B;B;B;B;B;.
Vest4		0.61
MutPred		0.74		Loss of glycosylation at S150 (P = 0.1795);Loss of glycosylation at S150 (P = 0.1795);Loss of glycosylation at S150 (P = 0.1795);Loss of glycosylation at S150 (P = 0.1795);Loss of glycosylation at S150 (P = 0.1795);Loss of glycosylation at S150 (P = 0.1795);
MVP		0.30
MPC		0.22
ClinPred		0.023	T
GERP RS		-1.1
Varity_R		0.074
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs386833816; hg19: chr14-23282154;