Genetic Variant NM_000341.4:c.1684G>A (chr2-44320265-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000341.4(SLC3A1):c.1684G>A(p.Glu562Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC3A1
NM_000341.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.38

Variant links:

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 links:

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 links:

ENSG00000285542 (HGNC:):

ENSG00000285542 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC3A1	NM_000341.4 link	c.1684G>A	p.Glu562Lys	missense_variant	Exon 10 of 10	ENST00000260649.11	NP_000332.2	Q07837-1A0A0S2Z4E1
PREPL	NM_001171613.2 link	c.*1091C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000409411.6	NP_001165084.1	Q4J6C6-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC3A1	ENST00000260649.11 link	c.1684G>A	p.Glu562Lys	missense_variant	Exon 10 of 10	1	NM_000341.4	ENSP00000260649.6	Q07837-1
PREPL	ENST00000409411 link	c.*1091C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_001171613.2	ENSP00000387095.2	Q4J6C6-4
ENSG00000285542	ENST00000649044.1 link	n.*1695G>A		non_coding_transcript_exon_variant	Exon 15 of 15			ENSP00000497083.1	A0A3B3IS24
ENSG00000285542	ENST00000649044.1 link	n.*1695G>A		3_prime_UTR_variant	Exon 15 of 15			ENSP00000497083.1	A0A3B3IS24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.024

D;D;D

Sift4G

Benign

0.16

T;T;T

Polyphen

0.85

P;.;.

Vest4

0.70

MutPred

0.58

Gain of ubiquitination at E562 (P = 0.0388);.;.;

MVP

0.98

MPC

0.017

ClinPred

0.96

GERP RS

6.2

Varity_R

0.35

gMVP

0.79

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over