rs79389353

Variant names:

• chr19-32862521-C-T
• rs79389353
• NM_014270.5:c.544G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-32862521-C-T
• chr19-32862521-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP5 BP4 BS1_Supporting BS2

The NM_014270.5(SLC7A9):​c.544G>A​(p.Ala182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,704 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A182V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (15 hom.)
• Consequence: SLC7A9 NM_014270.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19 U:1
• Conservation: PhyloP100: 1.64
• Publications: 28 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014270.5
• PP5: Variant 19-32862521-C-T is Pathogenic according to our data. Variant chr19-32862521-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5782.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013428539). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00236 (360/152240) while in subpopulation NFE AF = 0.00426 (290/68020). AF 95% confidence interval is 0.00386. There are 2 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

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.544G>A	p.Ala182Thr	missense	Exon 5 of 13	NP_055085.1	P82251
	SLC7A9	NM_001126335.2		c.544G>A	p.Ala182Thr	missense	Exon 5 of 13	NP_001119807.1	P82251
	SLC7A9	NM_001243036.2		c.544G>A	p.Ala182Thr	missense	Exon 5 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.544G>A	p.Ala182Thr	missense	Exon 5 of 13	ENSP00000023064.3	P82251
	SLC7A9	ENST00000587772.1	TSL:1	c.544G>A	p.Ala182Thr	missense	Exon 5 of 13	ENSP00000468439.1	P82251
	SLC7A9	ENST00000590341.5	TSL:1	c.544G>A	p.Ala182Thr	missense	Exon 5 of 13	ENSP00000464822.1	P82251

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00262 AC: 660 AN: 251440 AF XY: 0.00267

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00425 AC: 6206 AN: 1461464 Hom.: 15 Cov.: 39 AF XY: 0.00418 AC XY: 3036 AN XY: 727018

African (AFR) AF: 0.000777 AC: 26 AN: 33470

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26134

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

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86234

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53408

Middle Eastern (MID) AF: 0.00202 AC: 11 AN: 5454

European-Non Finnish (NFE) AF: 0.00506 AC: 5626 AN: 1111996

Other (OTH) AF: 0.00419 AC: 253 AN: 60344

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152240 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74420

African (AFR) AF: 0.000553 AC: 23 AN: 41558

American (AMR) AF: 0.000720 AC: 11 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00390 Hom.: 7

Bravo AF: 0.00249

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
15	-	-	Cystinuria (15)
2	1	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	SLC7A9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.50
Sift	Benign	0.085	T
Sift4G	Benign	0.31	T
Polyphen		0.12	B
Vest4		0.23
MVP		0.88
MPC		0.30
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.69
Mutation Taster		=75/25	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: rs79389353; hg19: chr19-33353427; COSMIC: COSV50086472; COSMIC: COSV50086472;