3-121896409-A-G

Variant names:

• chr3-121896409-A-G
• rs772586094
• NM_021082.4:c.109A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021082.4(SLC15A2):​c.109A>G​(p.Ile37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC15A2 NM_021082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC15A2	NM_021082.4	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 22	ENST00000489711.6	NP_066568.3
SLC15A2	NM_001145998.2	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 21		NP_001139470.1
SLC15A2	XM_005247722.4	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 21		XP_005247779.1
SLC15A2	XM_006713736.4	c.109A>G	p.Ile37Val	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.109A>G	p.Ile37Val	missense_variant	Exon 2 of 22	1	NM_021082.4	ENSP00000417085.1
SLC15A2	ENST00000295605.6	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 21	2		ENSP00000295605.2
SLC15A2	ENST00000469013	c.-78A>G		5_prime_UTR_variant	Exon 2 of 7	4		ENSP00000418704.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251302 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135814

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460554 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726716

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109A>G (p.I37V) alteration is located in exon 2 (coding exon 2) of the SLC15A2 gene. This alteration results from a A to G substitution at nucleotide position 109, causing the isoleucine (I) at amino acid position 37 to be replaced by a valine (V). 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	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.059	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.020
Sift	Benign	0.43	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.012	B;.
Vest4		0.12
MutPred		0.21		Loss of ubiquitination at K32 (P = 0.1278);Loss of ubiquitination at K32 (P = 0.1278);
MVP		0.50
MPC		0.067
ClinPred		0.019	T
GERP RS		2.9
Varity_R		0.023
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs772586094; hg19: chr3-121615256; COSMIC: COSV55201180;