19-32830681-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014270.5(SLC7A9):c.1403C>T(p.Pro468Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,602 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P468S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: SLC7A9 NM_014270.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.00

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008548379).
• BP6: Variant 19-32830681-G-A is Benign according to our data. Variant chr19-32830681-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00104 (1518/1461310) while in subpopulation AMR AF= 0.0167 (746/44722). AF 95% confidence interval is 0.0157. There are 14 homozygotes in gnomad4_exome. There are 745 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A9	NM_014270.5	c.1403C>T	p.Pro468Leu	missense_variant	13/13	ENST00000023064.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A9	ENST00000023064.9	c.1403C>T	p.Pro468Leu	missense_variant	13/13	1	NM_014270.5	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00317 AC: 797 AN: 251482 Hom.: 8 AF XY: 0.00260 AC XY: 353 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00696

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00104 AC: 1518 AN: 1461310 Hom.: 14 Cov.: 30 AF XY: 0.00102 AC XY: 745 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74458

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000882 Hom.: 1

Bravo AF: 0.00176

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	-0.019
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.15	B;B;B
Vest4		0.67
MVP		0.91
MPC		0.55
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.13
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80283711; hg19: chr19-33321587; COSMIC: COSV50084637; COSMIC: COSV50084637;