rs121912695

Positions:

• chr2-44320536-C-G
• chr2-44320536-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000341.4(SLC3A1):​c.1955C>G​(p.Thr652Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.533

Genes affected

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 2-44320536-C-G is Pathogenic according to our data. Variant chr2-44320536-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 18119.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.1955C>G	p.Thr652Arg	missense_variant	10/10	ENST00000260649.11	NP_000332.2
PREPL	NM_001171613.2	c.*820G>C		3_prime_UTR_variant	14/14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.1955C>G	p.Thr652Arg	missense_variant	10/10	1	NM_000341.4	ENSP00000260649.6
PREPL	ENST00000409411	c.*820G>C		3_prime_UTR_variant	14/14	1	NM_001171613.2	ENSP00000387095.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461730 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cystinuria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.061	B;.;.
Vest4		0.26
MutPred		0.81		Loss of catalytic residue at T652 (P = 0.0393);.;.;
MVP		0.87
MPC		0.0083
ClinPred		0.38	T
GERP RS		0.22
Varity_R		0.30
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912695; hg19: chr2-44547675;