12-128823505-C-G

Variant summary

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

The NM_145648.4(SLC15A4):c.439G>C(p.Asp147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,331,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D147A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SLC15A4 NM_145648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.195

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=0.15776664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC15A4	NM_145648.4	c.439G>C	p.Asp147His	missense_variant	1/8	ENST00000266771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC15A4	ENST00000266771.10	c.439G>C	p.Asp147His	missense_variant	1/8	1	NM_145648.4	P1
SLC15A4	ENST00000539703.1	n.89G>C		non_coding_transcript_exon_variant	1/4	5
SLC15A4	ENST00000376744.8	c.277G>C	p.Asp93His	missense_variant, NMD_transcript_variant	1/7	2
SLC15A4	ENST00000376740.8	c.19G>C	p.Asp7His	missense_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1331390 Hom.: 0 Cov.: 32 AF XY: 0.00000305 AC XY: 2 AN XY: 656296

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: 0.00000189

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

Mar 07, 2024

The c.439G>C (p.D147H) alteration is located in exon 1 (coding exon 1) of the SLC15A4 gene. This alteration results from a G to C substitution at nucleotide position 439, causing the aspartic acid (D) at amino acid position 147 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.087
Sift	Benign	0.053	T
Sift4G	Benign	0.10	T
Polyphen		0.90	P
Vest4		0.16
MutPred		0.50		Loss of solvent accessibility (P = 0.0703);
MVP		0.16
MPC		0.66
ClinPred		0.24	T
GERP RS		0.89
Varity_R		0.080
gMVP		0.43

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: rs1454193418; hg19: chr12-129308050;