chr2-44320435-G-A

Position:

• chr2-44320435-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000341.4(SLC3A1):​c.1854G>A​(p.Met618Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,640 control chromosomes in the GnomAD database, including 349,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.53 (24251 hom., cov: 33)
  • Exomes 𝑓: 0.66 (324999 hom.)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:5
• Conservation: PhyloP100: -0.144

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6894764E-6).
• BP6: Variant 2-44320435-G-A is Benign according to our data. Variant chr2-44320435-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336214.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Pathogenic=1}. Variant chr2-44320435-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.1854G>A	p.Met618Ile	missense_variant	10/10	ENST00000260649.11	NP_000332.2
PREPL	NM_001171613.2	c.*921C>T		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.1854G>A	p.Met618Ile	missense_variant	10/10	1	NM_000341.4	ENSP00000260649	P1
PREPL	ENST00000409411.6	c.*921C>T		3_prime_UTR_variant	14/14	1	NM_001171613.2	ENSP00000387095	P4

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81262 AN: 151978 Hom.: 24260 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.594 AC: 148070 AN: 249352 Hom.: 46493 AF XY: 0.609 AC XY: 82177 AN XY: 134918

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.312

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.660 AC: 964425 AN: 1461544 Hom.: 324999 Cov.: 50 AF XY: 0.662 AC XY: 481119 AN XY: 727116

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.684

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.692

Gnomad4 OTH exome AF: 0.624

GnomAD4 genome AF: 0.534 AC: 81251 AN: 152096 Hom.: 24251 Cov.: 33 AF XY: 0.529 AC XY: 39348 AN XY: 74330

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.563

Alfa AF: 0.658 Hom.: 77825

Bravo AF: 0.516

TwinsUK AF: 0.698 AC: 2587

ALSPAC AF: 0.694 AC: 2673

ESP6500AA AF: 0.288 AC: 1270

ESP6500EA AF: 0.676 AC: 5817

ExAC AF: 0.596 AC: 72332

Asia WGS AF: 0.475 AC: 1655 AN: 3478

EpiCase AF: 0.692

EpiControl AF: 0.686

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystinuria Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -
Pathogenic, 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 missense variant (M618I) in the SLC3A1 gene, as a pathogenic variant, by using the technique of Next-generation sequencing. The variant was potentially involved in causing Cystinuria by altering the structural and functional effect of the rBAT protein coded by the SLC3A1 gene. The variant was confirmed by ARMS-PCR at the population level (Zafar & Awais, 2023). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.8
DANN	Benign	0.66
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0000037	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.77	N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.042
MutPred		0.15		Loss of methylation at R619 (P = 0.0934);.;.;
MPC		0.0062
ClinPred		0.0026	T
GERP RS		-1.4
Varity_R		0.097
gMVP		0.50

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: rs698761; hg19: chr2-44547574; COSMIC: COSV53215689; COSMIC: COSV53215689;