12-128794203-C-T

Position:

• chr12-128794203-C-T

Variant summary

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

The NM_145648.4(SLC15A4):​c.1727G>A​(p.Arg576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: SLC15A4 NM_145648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09635937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC15A4	NM_145648.4	c.1727G>A	p.Arg576Lys	missense_variant	8/8	ENST00000266771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC15A4	ENST00000266771.10	c.1727G>A	p.Arg576Lys	missense_variant	8/8	1	NM_145648.4	P1
SLC15A4	ENST00000544112.5	n.1601G>A		non_coding_transcript_exon_variant	5/5	2
SLC15A4	ENST00000545031.5	n.1161G>A		non_coding_transcript_exon_variant	3/3	2
SLC15A4	ENST00000376744.8	c.*679G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Aug 30, 2022

The c.1727G>A (p.R576K) alteration is located in exon 8 (coding exon 8) of the SLC15A4 gene. This alteration results from a G to A substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.031
Sift	Benign	0.044	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.20		Gain of methylation at R576 (P = 0.0198);
MVP		0.061
MPC		0.52
ClinPred		0.17	T
GERP RS		2.9
Varity_R		0.21
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1955418654; hg19: chr12-129278748; COSMIC: COSV57163438;