2-44275649-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000341.4(SLC3A1):c.114A>C(p.Gly38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,613,626 control chromosomes in the GnomAD database, including 480,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43627 hom., cov: 33)
  • Exomes 𝑓: 0.77 (436813 hom.)
• Consequence: SLC3A1 NM_000341.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0880

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 2-44275649-A-C is Benign according to our data. Variant chr2-44275649-A-C is described in ClinVar as [Benign]. Clinvar id is 336184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44275649-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.088 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC3A1	NM_000341.4	c.114A>C	p.Gly38=	synonymous_variant	1/10	ENST00000260649.11
SLC3A1	XM_011533047.4	c.114A>C	p.Gly38=	synonymous_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC3A1	ENST00000260649.11	c.114A>C	p.Gly38=	synonymous_variant	1/10	1	NM_000341.4	P1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114387 AN: 152090 Hom.: 43579 Cov.: 33

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.723 AC: 181054 AN: 250552 Hom.: 67633 AF XY: 0.735 AC XY: 99502 AN XY: 135426

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.355

Gnomad SAS exome AF: 0.854

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.745

GnomAD4 exome AF: 0.769 AC: 1123652 AN: 1461418 Hom.: 436813 Cov.: 61 AF XY: 0.772 AC XY: 560974 AN XY: 726974

Gnomad4 AFR exome AF: 0.802

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.397

Gnomad4 SAS exome AF: 0.854

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.760

GnomAD4 genome AF: 0.752 AC: 114494 AN: 152208 Hom.: 43627 Cov.: 33 AF XY: 0.746 AC XY: 55476 AN XY: 74414

Gnomad4 AFR AF: 0.796

Gnomad4 AMR AF: 0.688

Gnomad4 ASJ AF: 0.799

Gnomad4 EAS AF: 0.355

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.775

Gnomad4 OTH AF: 0.751

Alfa AF: 0.770 Hom.: 91592

Bravo AF: 0.747

Asia WGS AF: 0.642 AC: 2236 AN: 3478

EpiCase AF: 0.786

EpiControl AF: 0.782

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	research	Biotechnology Lab, University of Central Punjab	Feb 10, 2023	A molecular and computational study performed on the Pakistani population reported this synonymous variant (G38=) in the SLC3A1 gene, as a benign variant, by using the technique of Next-generation sequencing. This variant might be the reason for causing the disease or increasing the severity of the already inherited Cystinuria. The variant was confirmed by ARMS-PCR at the population level (Zafar & Awais, 2023). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	2.2
Dann	Benign	0.31

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: rs3738985; hg19: chr2-44502788; COSMIC: COSV53222180; COSMIC: COSV53222180;