chr2-44320241-G-T

Variant names:

• chr2-44320241-G-T
• rs1418838313
• NM_000341.4:c.1660G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000341.4(SLC3A1):​c.1660G>T​(p.Asp554Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89
• Publications: 1 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), Illumina, Ambry Genetics

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.1660G>T	p.Asp554Tyr	missense	Exon 10 of 10	NP_000332.2	Q07837-1
	PREPL	NM_001171613.2	MANE Select	c.*1115C>A		3_prime_UTR	Exon 14 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.*1115C>A		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.1660G>T	p.Asp554Tyr	missense	Exon 10 of 10	ENSP00000260649.6	Q07837-1
	SLC3A1	ENST00000409380.5	TSL:1	c.826G>T	p.Asp276Tyr	missense	Exon 7 of 7	ENSP00000386709.1	Q07837-2
	SLC3A1	ENST00000409740.3	TSL:1	c.553G>T	p.Asp185Tyr	missense	Exon 4 of 4	ENSP00000386677.3	Q07837-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251156 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cystinuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.37
Sift	Benign	0.038	D
Sift4G	Uncertain	0.025	D
Polyphen		0.16	B
Vest4		0.20
MutPred		0.49		Gain of methylation at K550 (P = 0.0691)
MVP		0.91
MPC		0.0069
ClinPred		0.53	D
GERP RS		4.2
Varity_R		0.21
gMVP		0.65
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1418838313; hg19: chr2-44547380; COSMIC: COSV53219172; COSMIC: COSV53219172;