rs121908480

Variant names:

• chr19-32864261-C-T
• rs121908480
• NM_014270.5:c.313G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3 PP3 PP5_Very_Strong BS2_Supporting

The NM_014270.5(SLC7A9):​c.313G>A​(p.Gly105Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000493 in 1,614,134 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000914836: Functional studies in HeLa cells showed the variant reduced protein expression and amino acid transport activity to ten percent of wild type (Font et al. 2001)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (3 hom.)
• Consequence: SLC7A9 NM_014270.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 6.17
• Publications: 31 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• cystinuria type B

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914836: Functional studies in HeLa cells showed the variant reduced protein expression and amino acid transport activity to ten percent of wild type (Font et al. 2001).; SCV005398478: "In vitro assays demonstrated reduced cysteine transport (PMID: 11157794)."; SCV000616881: Published functional studies demonstrate a damaging effect due to almost completely abolishing the amino acid transport activity of the protein, retaining only approximately 10% of wild-type transport activity (Font et al., 2001).; SCV001385883: Experimental studies have shown that this missense change affects SLC7A9 function (PMID: 11157794).; SCV002822542: PS3:Supporting; SCV005355359: Functional studies indicate that the p.Gly105Arg protein variant only has 10% activity of the wild type protein which results in impaired cystine transport and a more severe urinary phenotype (Font et al. 2001. PubMed ID: 11157794).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 19-32864261-C-T is Pathogenic according to our data. Variant chr19-32864261-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,SD,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014270.5. 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
	SLC7A9	NM_014270.5	MANE Select	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	NP_055085.1	P82251
	SLC7A9	NM_001126335.2		c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	NP_001119807.1	P82251
	SLC7A9	NM_001243036.2		c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	NP_001229965.1	P82251

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A9	ENST00000023064.9	TSL:1 MANE Select	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	ENSP00000023064.3	P82251
	SLC7A9	ENST00000587772.1	TSL:1	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	ENSP00000468439.1	P82251
	SLC7A9	ENST00000590341.5	TSL:1	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	ENSP00000464822.1	P82251

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251028 AF XY: 0.000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000524 AC: 766 AN: 1461838 Hom.: 3 Cov.: 34 AF XY: 0.000532 AC XY: 387 AN XY: 727226

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000656 AC: 729 AN: 1111998

Other (OTH) AF: 0.000331 AC: 20 AN: 60388

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68006

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000354 Hom.: 1

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Cystinuria (12)
5	-	-	not provided (5)
1	-	-	SLC7A9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Gain of solvent accessibility (P = 0.0584)
MVP		0.98
MPC		1.1
ClinPred		0.59	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.96
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908480; hg19: chr19-33355167;