3-121896437-T-C

Variant names:

• chr3-121896437-T-C
• NM_021082.4:c.137T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021082.4(SLC15A2):​c.137T>C​(p.Ile46Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC15A2 NM_021082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

Genes affected

SLC15A2 (HGNC:10921): (solute carrier family 15 member 2) The mammalian kidney expresses a proton-coupled peptide transporter that is responsible for the absorption of small peptides, as well as beta-lactam antibiotics and other peptide-like drugs, from the tubular filtrate. This transporter, SLC15A2, belongs to the same gene family as SLC15A1 (MIM 600544), the proton-coupled peptide transporter found in the small intestine (Liu et al, 1995 [PubMed 7756356]).[supplied by OMIM, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC15A2	NM_021082.4	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 22	ENST00000489711.6	NP_066568.3
SLC15A2	NM_001145998.2	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 21		NP_001139470.1
SLC15A2	XM_005247722.4	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 21		XP_005247779.1
SLC15A2	XM_006713736.4	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 19		XP_006713799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC15A2	ENST00000489711.6	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 22	1	NM_021082.4	ENSP00000417085.1
SLC15A2	ENST00000469013	c.-50T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7	4		ENSP00000418704.1
SLC15A2	ENST00000295605.6	c.137T>C	p.Ile46Thr	missense_variant	Exon 2 of 21	2		ENSP00000295605.2
SLC15A2	ENST00000469013	c.-50T>C		5_prime_UTR_variant	Exon 2 of 7	4		ENSP00000418704.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137T>C (p.I46T) alteration is located in exon 2 (coding exon 2) of the SLC15A2 gene. This alteration results from a T to C substitution at nucleotide position 137, causing the isoleucine (I) at amino acid position 46 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.87	P;.
Vest4		0.94
MutPred		0.62		Gain of glycosylation at I46 (P = 0.0073);Gain of glycosylation at I46 (P = 0.0073);
MVP		0.76
MPC		0.14
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.75

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.

Other links and lift over

hg19: chr3-121615284;