rs386833817

Variant names:

• chr14-22812899-C-G
• rs386833817
• NM_003982.4:c.499+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-22812899-C-G
• chr14-22812899-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_003982.4(SLC7A7):​c.499+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC7A7 NM_003982.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.35221353 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 15, new splice context is: gggGTagga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 14-22812899-C-G is Pathogenic according to our data. Variant chr14-22812899-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3383994.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	NM_003982.4	MANE Select	c.499+1G>C		splice_donor intron	N/A	NP_003973.3
	SLC7A7	NM_001126105.3		c.499+1G>C		splice_donor intron	N/A	NP_001119577.1	A0A0S2Z502
	SLC7A7	NM_001126106.4		c.499+1G>C		splice_donor intron	N/A	NP_001119578.1	Q9UM01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	ENST00000674313.1	MANE Select	c.499+1G>C		splice_donor intron	N/A	ENSP00000501493.1	Q9UM01
	SLC7A7	ENST00000397528.8	TSL:1	c.499+1G>C		splice_donor intron	N/A	ENSP00000380662.4	Q9UM01
	SLC7A7	ENST00000397529.6	TSL:1	c.499+1G>C		splice_donor intron	N/A	ENSP00000380663.2	Q9UM01

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151706 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461156 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52812

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151706 Hom.: 0 Cov.: 29 AF XY: 0.0000270 AC XY: 2 AN XY: 74086

African (AFR) AF: 0.00 AC: 0 AN: 41238

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Lysinuric protein intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.9
GERP RS		5.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386833817; hg19: chr14-23282108;