12-128808922-A-G

Variant summary

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

The NM_145648.4(SLC15A4):ā€‹c.1124T>Cā€‹(p.Val375Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

SLC15A4
NM_145648.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.46
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 Protein UniProt
SLC15A4NM_145648.4 linkuse as main transcriptc.1124T>C p.Val375Ala missense_variant 5/8 ENST00000266771.10 NP_663623.1 Q8N697-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC15A4ENST00000266771.10 linkuse as main transcriptc.1124T>C p.Val375Ala missense_variant 5/81 NM_145648.4 ENSP00000266771.5 Q8N697-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152242
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251330
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461818
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152242
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 25, 2024The c.1124T>C (p.V375A) alteration is located in exon 5 (coding exon 5) of the SLC15A4 gene. This alteration results from a T to C substitution at nucleotide position 1124, causing the valine (V) at amino acid position 375 to be replaced by an alanine (A). 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
-0.16
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.16
T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.57
D
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.0
M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.3
D
REVEL
Benign
0.25
Sift
Benign
0.048
D
Sift4G
Uncertain
0.038
D
Polyphen
0.69
P
Vest4
0.67
MVP
0.31
MPC
0.79
ClinPred
0.55
D
GERP RS
4.4
Varity_R
0.37
gMVP
0.71

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764487485; hg19: chr12-129293467; API