rs1007096305

Variant names:

• chr19-32833195-G-T
• rs1007096305
• NM_014270.5:c.1353C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_014270.5(SLC7A9):​c.1353C>A​(p.Tyr451*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC7A9 NM_014270.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.11
• Publications: 1 publications found

Genes affected

SLC7A9 (HGNC:11067): (solute carrier family 7 member 9) This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. Alternate transcript variants, which encode the same protein, have been found for this gene. [provided by RefSeq, Jul 2011]

SLC7A9 Gene-Disease associations (from GenCC):

• cystinuria

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• cystinuria type B

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267555 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0758 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 19-32833195-G-T is Pathogenic according to our data. Variant chr19-32833195-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 562455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A9	NM_014270.5	c.1353C>A	p.Tyr451*	stop_gained	Exon 12 of 13	ENST00000023064.9	NP_055085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A9	ENST00000023064.9	c.1353C>A	p.Tyr451*	stop_gained	Exon 12 of 13	1	NM_014270.5	ENSP00000023064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SLC7A9 are known to be pathogenic (PMID: 11157794). This variant has been observed in combination with another SLC7A9 variant in an individual affected with cystinuria type B (PMID: 25296721). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr451*) in the SLC7A9 gene. It is expected to result in an absent or disrupted protein product. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cystinuria Pathogenic:1

Aug 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.1
Vest4		0.88
GERP RS		3.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1007096305; hg19: chr19-33324101;