2-44301128-GT-G

Variant names:

• chr2-44301128-GT-G
• rs796262035
• ENST00000410056.7:c.1139delT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The ENST00000410056.7(SLC3A1):​c.1139delT​(p.Leu380fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 1,613,908 control chromosomes in the GnomAD database, including 9,573 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L380L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.14 (1770 hom., cov: 30)
  • Exomes 𝑓: 0.096 (7803 hom.)
• Consequence: SLC3A1 ENST00000410056.7 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 5 publications found

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]

SLC3A1 Gene-Disease associations (from GenCC):

• cystinuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• cystinuria type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0315 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 2-44301128-GT-G is Benign according to our data. Variant chr2-44301128-GT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 336199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.1136+3delT		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4	c.1136+3delT		splice_region_variant, intron_variant	Intron 6 of 9		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.1136+3delT		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_000341.4	ENSP00000260649.6
ENSG00000285542	ENST00000649044.1	n.*1147+3delT		splice_region_variant, intron_variant	Intron 11 of 14			ENSP00000497083.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20672 AN: 152022 Hom.: 1763 Cov.: 30

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.0880

Gnomad ASJ AF: 0.0858

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0875 AC: 21977 AN: 251244 AF XY: 0.0830

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.0849

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0903

GnomAD4 exome AF: 0.0962 AC: 140568 AN: 1461768 Hom.: 7803 Cov.: 30 AF XY: 0.0936 AC XY: 68053 AN XY: 727188

African (AFR) AF: 0.252 AC: 8431 AN: 33478

American (AMR) AF: 0.0641 AC: 2867 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0840 AC: 2196 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0199 AC: 1718 AN: 86256

European-Finnish (FIN) AF: 0.0990 AC: 5289 AN: 53420

Middle Eastern (MID) AF: 0.0534 AC: 308 AN: 5768

European-Non Finnish (NFE) AF: 0.102 AC: 113734 AN: 1111896

Other (OTH) AF: 0.0997 AC: 6023 AN: 60394

GnomAD4 genome AF: 0.136 AC: 20715 AN: 152140 Hom.: 1770 Cov.: 30 AF XY: 0.134 AC XY: 9944 AN XY: 74374

African (AFR) AF: 0.246 AC: 10215 AN: 41470

American (AMR) AF: 0.0878 AC: 1343 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0858 AC: 298 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1075 AN: 10588

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7304 AN: 68004

Other (OTH) AF: 0.122 AC: 258 AN: 2114

Alfa AF: 0.0334 Hom.: 219

Bravo AF: 0.142

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 242/2178=11.1% -

not provided Benign:1

Feb 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=20/80	polymorphism (auto)

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: rs796262035; hg19: chr2-44528267; COSMIC: COSV53220834; COSMIC: COSV53220834;