NM_003982.4:c.499+1G>C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_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

Variant links:

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

SLC7A7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-22812899-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 3383994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC7A7	NM_003982.4 link	c.499+1G>C	splice_donor_variant, intron_variant	Intron 2 of 9	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3 link	c.499+1G>C	splice_donor_variant, intron_variant	Intron 3 of 10		NP_001119577.1	Q9UM01A0A0S2Z502
SLC7A7	NM_001126106.4 link	c.499+1G>C	splice_donor_variant, intron_variant	Intron 3 of 10		NP_001119578.1	Q9UM01A0A0S2Z502
SLC7A7	XM_011537299.2 link	c.499+1G>C	splice_donor_variant, intron_variant	Intron 2 of 9		XP_011535601.1	Q9UM01A0A0S2Z502

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1 link	c.499+1G>C		splice_donor_variant, intron_variant	Intron 2 of 9		NM_003982.4	ENSP00000501493.1		Q9UM01

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151706

Hom.:

Cov.:

show subpopulations

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:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151706

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41238

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lysinuric protein intolerance

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1,PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.95

PhyloP100

7.9

GERP RS

5.7

Mutation Taster

=1/99

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over