rs698761

Variant names:

• chr2-44320435-G-A
• rs698761
• NM_000341.4:c.1854G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-44320435-G-A
• chr2-44320435-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM5 PP2 BP4_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M618T) has been classified as Likely pathogenic.

• 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
• Publications: 46 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]

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]

PREPL Gene-Disease associations (from GenCC):

• hypotonia-cystinuria syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• myasthenic syndrome, congenital, 22

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, PanelApp Australia

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-44320434-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4526821.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -3.1434 (below the threshold of 3.09). Trascript score misZ: -3.2509 (below the threshold of 3.09). GenCC associations: The gene is linked to cystinuria type A, cystinuria.
• BP4: Computational evidence support a benign effect (MetaRNN=3.6894764E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000341.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC3A1	NM_000341.4	MANE Select	c.1854G>A	p.Met618Ile	missense	Exon 10 of 10	NP_000332.2	Q07837-1
	PREPL	NM_001171613.2	MANE Select	c.*921C>T		3_prime_UTR	Exon 14 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.*921C>T		3_prime_UTR	Exon 15 of 15	NP_001165074.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC3A1	ENST00000260649.11	TSL:1 MANE Select	c.1854G>A	p.Met618Ile	missense	Exon 10 of 10	ENSP00000260649.6	Q07837-1
	SLC3A1	ENST00000409380.5	TSL:1	c.1020G>A	p.Met340Ile	missense	Exon 7 of 7	ENSP00000386709.1	Q07837-2
	SLC3A1	ENST00000409740.3	TSL:1	c.747G>A	p.Met249Ile	missense	Exon 4 of 4	ENSP00000386677.3	Q07837-4

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

GnomAD2 exomes AF: 0.594 AC: 148070 AN: 249352 AF XY: 0.609

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 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

African (AFR) AF: 0.262 AC: 8759 AN: 33474

American (AMR) AF: 0.519 AC: 23213 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 17860 AN: 26128

East Asian (EAS) AF: 0.357 AC: 14185 AN: 39692

South Asian (SAS) AF: 0.664 AC: 57314 AN: 86252

European-Finnish (FIN) AF: 0.598 AC: 31924 AN: 53406

Middle Eastern (MID) AF: 0.680 AC: 3923 AN: 5766

European-Non Finnish (NFE) AF: 0.692 AC: 769561 AN: 1111734

Other (OTH) AF: 0.624 AC: 37686 AN: 60382

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

African (AFR) AF: 0.272 AC: 11291 AN: 41478

American (AMR) AF: 0.556 AC: 8498 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2381 AN: 3470

East Asian (EAS) AF: 0.314 AC: 1628 AN: 5184

South Asian (SAS) AF: 0.649 AC: 3133 AN: 4824

European-Finnish (FIN) AF: 0.582 AC: 6148 AN: 10558

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46093 AN: 67984

Other (OTH) AF: 0.563 AC: 1191 AN: 2116

Alfa AF: 0.635 Hom.: 104648

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	3	Cystinuria (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000037	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.77	N
PhyloP100		-0.14
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.35	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
Mutation Taster		=98/2	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: rs698761; hg19: chr2-44547574; COSMIC: COSV53215689; COSMIC: COSV53215689;