3-183152491-G-A

Variant names:

• chr3-183152491-G-A
• rs1369423682
• NM_014398.4:c.772C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014398.4(LAMP3):​c.772C>T​(p.Arg258Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,609,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAMP3 NM_014398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24736542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP3	NM_014398.4	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 6	ENST00000265598.8	NP_055213.2
LAMP3	XM_005247360.6	c.772C>T	p.Arg258Trp	missense_variant	Exon 4 of 7		XP_005247417.1
LAMP3	XM_047447967.1	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 6		XP_047303923.1
LAMP3	XM_011512688.3	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 6		XP_011510990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP3	ENST00000265598.8	c.772C>T	p.Arg258Trp	missense_variant	Exon 3 of 6	1	NM_014398.4	ENSP00000265598.3
LAMP3	ENST00000466939.1	c.700C>T	p.Arg234Trp	missense_variant	Exon 3 of 6	2		ENSP00000418912.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457292 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725078

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 85560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110380

Other (OTH) AF: 0.0000166 AC: 1 AN: 60188

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41414

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.772C>T (p.R258W) alteration is located in exon 3 (coding exon 3) of the LAMP3 gene. This alteration results from a C to T substitution at nucleotide position 772, causing the arginine (R) at amino acid position 258 to be replaced by a tryptophan (W). 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	0.098
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	0.0048
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.
PhyloP100		1.9
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.63		Gain of sheet (P = 0.0221);.;
MVP		0.068
MPC		0.27
ClinPred		0.74	D
GERP RS		2.5
Varity_R		0.36
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1369423682; hg19: chr3-182870279; COSMIC: COSV55614133; COSMIC: COSV55614133;