Variant 12-128799415-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145648.4(SLC15A4):c.1417C>A(p.Leu473Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SLC15A4
NM_145648.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.03

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]

SLC15A4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC15A4	NM_145648.4 linkuse as main transcript	c.1417C>A	p.Leu473Met	missense_variant, splice_region_variant	7/8	ENST00000266771.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC15A4	ENST00000266771.10 linkuse as main transcript	c.1417C>A	p.Leu473Met	missense_variant, splice_region_variant	7/8	1	NM_145648.4	P1	Q8N697-1
SLC15A4	ENST00000544112.5 linkuse as main transcript	n.1291C>A		splice_region_variant, non_coding_transcript_exon_variant	4/5	2
SLC15A4	ENST00000545031.5 linkuse as main transcript	n.851C>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
SLC15A4	ENST00000376744.8 linkuse as main transcript	c.*369C>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

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:

0.0000301

Hom.:

Bravo

AF:

0.0000189

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 submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1417C>A (p.L473M) alteration is located in exon 7 (coding exon 7) of the SLC15A4 gene. This alteration results from a C to A substitution at nucleotide position 1417, causing the leucine (L) at amino acid position 473 to be replaced by a methionine (M). 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

0.57

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.80

MutPred

0.67

Gain of disorder (P = 0.059);

MVP

0.25

MPC

1.4

ClinPred

0.92

GERP RS

4.4

Varity_R

0.55

gMVP

0.73

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over