12-128823576-A-T

Variant summary

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

The NM_145648.4(SLC15A4):c.368T>A(p.Leu123Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000774 in 1,291,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SLC15A4 NM_145648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

Genes affected

SLC15A4 (HGNC:23090): (solute carrier family 15 member 4) Enables L-histidine transmembrane transporter activity; peptide transmembrane transporter activity; and peptidoglycan transmembrane transporter activity. Involved in several processes, including dipeptide import across plasma membrane; peptidoglycan transport; and positive regulation of toll-like receptor signaling pathway. Located in endolysosome membrane. Is integral component of lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
SLC15A4	NM_145648.4	c.368T>A	p.Leu123Gln	missense_variant	1/8	ENST00000266771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC15A4	ENST00000266771.10	c.368T>A	p.Leu123Gln	missense_variant	1/8	1	NM_145648.4	P1
SLC15A4	ENST00000539703.1	n.18T>A		non_coding_transcript_exon_variant	1/4	5
SLC15A4	ENST00000376744.8	c.206T>A	p.Leu69Gln	missense_variant, NMD_transcript_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.74e-7 AC: 1 AN: 1291966 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 636294

Gnomad4 AFR exome AF: 0.00

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: 0.0000187

GnomAD4 genome Cov.: 33

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

Feb 21, 2024

The c.368T>A (p.L123Q) alteration is located in exon 1 (coding exon 1) of the SLC15A4 gene. This alteration results from a T to A substitution at nucleotide position 368, causing the leucine (L) at amino acid position 123 to be replaced by a glutamine (Q). 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.23
Sift	Benign	0.033	D
Sift4G	Uncertain	0.015	D
Polyphen		0.90	P
Vest4		0.28
MutPred		0.51		Gain of catalytic residue at L123 (P = 0.0704);
MVP		0.61
MPC		1.3
ClinPred		0.66	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.42

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: chr12-129308121;