chr19-32830682-G-A

Variant names:

• chr19-32830682-G-A
• NM_014270.5:c.1402C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014270.5(SLC7A9):​c.1402C>T​(p.Pro468Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P468L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC7A9 NM_014270.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.91
• Publications: 0 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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• cystinuria type B

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 of 13	NP_055085.1	P82251
	SLC7A9	NM_001126335.2		c.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 of 13	NP_001119807.1	P82251
	SLC7A9	NM_001243036.2		c.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 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.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 of 13	ENSP00000023064.3	P82251
	SLC7A9	ENST00000587772.1	TSL:1	c.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 of 13	ENSP00000468439.1	P82251
	SLC7A9	ENST00000590341.5	TSL:1	c.1402C>T	p.Pro468Ser	missense splice_region	Exon 13 of 13	ENSP00000464822.1	P82251

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0075
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.50
Sift	Benign	0.85	T
Sift4G	Benign	0.94	T
Polyphen		0.029	B
Vest4		0.54
MutPred		0.28		Gain of MoRF binding (P = 0.0494)
MVP		0.88
MPC		0.63
ClinPred		0.60	D
GERP RS		5.7
Varity_R		0.092
gMVP		0.56
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

hg19: chr19-33321588;