19-32833149-T-G

Variant names:

• chr19-32833149-T-G
• rs201241670
• NM_014270.5:c.1399A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014270.5(SLC7A9):​c.1399A>C​(p.Lys467Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K467E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC7A9 NM_014270.5 missense, splice_region
• Scores: Splicing: ADA: 0.0008840
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 2 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

ENSG00000267555 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23213115).

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.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 of 13	NP_055085.1	P82251
	SLC7A9	NM_001126335.2		c.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 of 13	NP_001119807.1	P82251
	SLC7A9	NM_001243036.2		c.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 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.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 of 13	ENSP00000023064.3	P82251
	SLC7A9	ENST00000587772.1	TSL:1	c.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 of 13	ENSP00000468439.1	P82251
	SLC7A9	ENST00000590341.5	TSL:1	c.1399A>C	p.Lys467Gln	missense splice_region	Exon 12 of 13	ENSP00000464822.1	P82251

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251434 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.0094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.79	N
PhyloP100		2.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.27
Sift	Benign	0.71	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.47		Loss of methylation at K467 (P = 0.0086)
MVP		0.87
MPC		0.34
ClinPred		0.22	T
GERP RS		5.6
Varity_R		0.24
gMVP		0.49
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.066
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: rs201241670; hg19: chr19-33324055;