2-44275602-G-A

Variant names:

• chr2-44275602-G-A
• rs750919380
• NM_000341.4:c.67G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000341.4(SLC3A1):​c.67G>A​(p.Gly23Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,670 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.84

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]

ENSG00000285542 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 10	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 10		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 10	1	NM_000341.4	ENSP00000260649.6
ENSG00000285542	ENST00000649044.1	n.*78G>A		non_coding_transcript_exon_variant	Exon 6 of 15			ENSP00000497083.1
ENSG00000285542	ENST00000649044.1	n.*78G>A		3_prime_UTR_variant	Exon 6 of 15			ENSP00000497083.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251320 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135842

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727154

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Uncertain:2

Dec 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 23 of the SLC3A1 protein (p.Gly23Arg). This variant is present in population databases (rs750919380, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1462171). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.092	T;T;T;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	.;M;.;M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	.;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.79
MutPred		0.52		Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);
MVP		0.96
MPC		0.031
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs750919380; hg19: chr2-44502741;