NM_003982.4:c.1465T>C

Variant names:

• chr14-22773681-A-G
• rs386833810
• NM_003982.4:c.1465T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003982.4(SLC7A7):​c.1465T>C​(p.Ser489Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S489S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.95
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 14-22773681-A-G is Pathogenic according to our data. Variant chr14-22773681-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56362.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	NM_003982.4	MANE Select	c.1465T>C	p.Ser489Pro	missense	Exon 10 of 10	NP_003973.3
	SLC7A7	NM_001126105.3		c.1465T>C	p.Ser489Pro	missense	Exon 11 of 11	NP_001119577.1
	SLC7A7	NM_001126106.4		c.1465T>C	p.Ser489Pro	missense	Exon 11 of 11	NP_001119578.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	ENST00000674313.1	MANE Select	c.1465T>C	p.Ser489Pro	missense	Exon 10 of 10	ENSP00000501493.1
	SLC7A7	ENST00000397528.8	TSL:1	c.1465T>C	p.Ser489Pro	missense	Exon 11 of 11	ENSP00000380662.4
	SLC7A7	ENST00000397529.6	TSL:1	c.1465T>C	p.Ser489Pro	missense	Exon 10 of 10	ENSP00000380663.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Lysinuric protein intolerance (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.66
Sift	Benign	0.047	D
Sift4G	Benign	0.20	T
Polyphen		0.36	B
Vest4		0.76
MutPred		0.84		Loss of catalytic residue at S489 (P = 0.0042)
MVP		0.54
MPC		0.34
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.36
gMVP		0.60
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs386833810; hg19: chr14-23242890;