rs751299554

Variant names:

• chr3-183153715-C-T
• rs751299554
• NM_014398.4:c.726G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014398.4(LAMP3):​c.726G>A​(p.Met242Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000327 in 1,527,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: LAMP3 NM_014398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30
• Publications: 0 publications found

Genes affected

LAMP3 (HGNC:14582): (lysosomal associated membrane protein 3) Dendritic cells (DCs) are the most potent antigen-presenting cells. Immature DCs efficiently capture antigens and differentiate into interdigitating dendritic cells (IDCs) in lymphoid tissues that induce primary T-cell responses (summary by de Saint-Vis et al., 1998 [PubMed 9768752]).[supplied by OMIM, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP3	NM_014398.4	c.726G>A	p.Met242Ile	missense_variant	Exon 2 of 6	ENST00000265598.8	NP_055213.2
LAMP3	XM_005247360.6	c.726G>A	p.Met242Ile	missense_variant	Exon 3 of 7		XP_005247417.1
LAMP3	XM_047447967.1	c.726G>A	p.Met242Ile	missense_variant	Exon 2 of 6		XP_047303923.1
LAMP3	XM_011512688.3	c.726G>A	p.Met242Ile	missense_variant	Exon 2 of 6		XP_011510990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP3	ENST00000265598.8	c.726G>A	p.Met242Ile	missense_variant	Exon 2 of 6	1	NM_014398.4	ENSP00000265598.3
LAMP3	ENST00000466939.1	c.654G>A	p.Met218Ile	missense_variant	Exon 2 of 6	2		ENSP00000418912.1
LAMP3	ENST00000476015.1	c.*186G>A		downstream_gene_variant		4		ENSP00000419059.1
LAMP3	ENST00000470251.1	c.*225G>A		downstream_gene_variant		2		ENSP00000420589.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000492 AC: 9 AN: 182904 AF XY: 0.0000313

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000204 AC: 28 AN: 1375538 Hom.: 0 Cov.: 30 AF XY: 0.0000207 AC XY: 14 AN XY: 674960

African (AFR) AF: 0.000196 AC: 6 AN: 30594

American (AMR) AF: 0.0000322 AC: 1 AN: 31020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20202

East Asian (EAS) AF: 0.00 AC: 0 AN: 39016

South Asian (SAS) AF: 0.00 AC: 0 AN: 71124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.0000187 AC: 20 AN: 1071528

Other (OTH) AF: 0.0000177 AC: 1 AN: 56610

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74362

African (AFR) AF: 0.000482 AC: 20 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.726G>A (p.M242I) alteration is located in exon 2 (coding exon 2) of the LAMP3 gene. This alteration results from a G to A substitution at nucleotide position 726, causing the methionine (M) at amino acid position 242 to be replaced by an isoleucine (I). 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	0.72
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.019	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.96	P;.
Vest4		0.50
MutPred		0.72		Loss of ubiquitination at K239 (P = 0.1091);.;
MVP		0.19
MPC		0.38
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.34
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751299554; hg19: chr3-182871503;