rs778000327

Positions:

• chr2-44280876-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000341.4(SLC3A1):​c.592del​(p.Ala198GlnfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000409 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SLC3A1 NM_000341.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-44280876-TG-T is Pathogenic according to our data. Variant chr2-44280876-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.592del	p.Ala198GlnfsTer8	frameshift_variant	2/10	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4	c.592del	p.Ala198GlnfsTer8	frameshift_variant	2/10		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.592del	p.Ala198GlnfsTer8	frameshift_variant	2/10	1	NM_000341.4	ENSP00000260649	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251450 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135900

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000198 AC: 29 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727210

Gnomad4 AFR exome AF: 0.000687

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: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74350

Gnomad4 AFR AF: 0.000868

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000306

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 31, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 548674). This premature translational stop signal has been observed in individuals with cystinuria (PMID: 18947684, 28646536, 33262960). This variant is present in population databases (rs778000327, gnomAD 0.09%). This sequence change creates a premature translational stop signal (p.Ala198Glnfs*8) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). -
Pathogenic, criteria provided, single submitter	clinical testing	College of Medicine Research Centre, King Saud Univeristy	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -

Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 08, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25964309, 24610330, 28893421, 18947684, 28646536, 25109415, 33262960) -

Computational scores

Source: dbNSFP v4.3

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: rs778000327; hg19: chr2-44508015;