11-60941131-T-A

Position:

• chr11-60941131-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016582.3(SLC15A3):​c.1267A>T​(p.Ile423Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC15A3 NM_016582.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0370

Genes affected

SLC15A3 (HGNC:18068): (solute carrier family 15 member 3) Enables dipeptide transmembrane transporter activity. Involved in dipeptide import across plasma membrane. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

SLC15A3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17827767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC15A3	NM_016582.3	c.1267A>T	p.Ile423Phe	missense_variant	5/8	ENST00000227880.8	NP_057666.1
SLC15A3	XM_011545095.3	c.1267A>T	p.Ile423Phe	missense_variant	5/9		XP_011543397.1
SLC15A3	NR_027391.2	n.1732+904A>T		intron_variant
SLC15A3	XR_007062485.1	n.1732+904A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC15A3	ENST00000227880.8	c.1267A>T	p.Ile423Phe	missense_variant	5/8	1	NM_016582.3	ENSP00000227880.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460680 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 33

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

Dec 20, 2023

The c.1267A>T (p.I423F) alteration is located in exon 5 (coding exon 5) of the SLC15A3 gene. This alteration results from a A to T substitution at nucleotide position 1267, causing the isoleucine (I) at amino acid position 423 to be replaced by a phenylalanine (F). 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	0.14
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.0
DANN	Benign	0.70
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.18
Sift	Benign	0.68	T
Sift4G	Benign	0.56	T
Polyphen		0.94	P
Vest4		0.28
MutPred		0.58		Gain of catalytic residue at I423 (P = 0.0236);
MVP		0.62
MPC		0.52
ClinPred		0.27	T
GERP RS		0.52
Varity_R		0.096
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1856701803; hg19: chr11-60708603;