13-98704434-G-C

Position:

• chr13-98704434-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005073.4(SLC15A1):​c.1271C>G​(p.Thr424Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC15A1 NM_005073.4 missense, splice_region
• Scores: Splicing: ADA: 0.01131
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

SLC15A1 (HGNC:10920): (solute carrier family 15 member 1) This gene encodes an intestinal hydrogen peptide cotransporter that is a member of the solute carrier family 15. The encoded protein is localized to the brush border membrane of the intestinal epithelium and mediates the uptake of di- and tripeptides from the lumen into the enterocytes. This protein plays an important role in the uptake and digestion of dietary proteins. This protein also facilitates the absorption of numerous peptidomimetic drugs. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4013474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC15A1	NM_005073.4	c.1271C>G	p.Thr424Arg	missense_variant, splice_region_variant	17/23	ENST00000376503.10	NP_005064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC15A1	ENST00000376503.10	c.1271C>G	p.Thr424Arg	missense_variant, splice_region_variant	17/23	1	NM_005073.4	ENSP00000365686.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459516 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726030

Gnomad4 AFR exome AF: 0.0000300

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.1271C>G (p.T424R) alteration is located in exon 17 (coding exon 17) of the SLC15A1 gene. This alteration results from a C to G substitution at nucleotide position 1271, causing the threonine (T) at amino acid position 424 to be replaced by an arginine (R). 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	0.24
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Benign	0.26	T
Sift4G	Benign	0.42	T
Polyphen		0.0060	B
Vest4		0.48
MutPred		0.68		Gain of catalytic residue at T424 (P = 0.0466);
MVP		0.16
MPC		0.052
ClinPred		0.15	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1046793861; hg19: chr13-99356688;