3-183152454-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014398.4(LAMP3):c.809C>A(p.Ala270Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A270T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LAMP3 NM_014398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.965

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

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, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP3	NM_014398.4	c.809C>A	p.Ala270Asp	missense_variant	3/6	ENST00000265598.8
LAMP3	XM_005247360.6	c.809C>A	p.Ala270Asp	missense_variant	4/7
LAMP3	XM_047447967.1	c.809C>A	p.Ala270Asp	missense_variant	3/6
LAMP3	XM_011512688.3	c.809C>A	p.Ala270Asp	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP3	ENST00000265598.8	c.809C>A	p.Ala270Asp	missense_variant	3/6	1	NM_014398.4	P2
LAMP3	ENST00000466939.1	c.737C>A	p.Ala246Asp	missense_variant	3/6	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 15, 2021

The c.809C>A (p.A270D) alteration is located in exon 3 (coding exon 3) of the LAMP3 gene. This alteration results from a C to A substitution at nucleotide position 809, causing the alanine (A) at amino acid position 270 to be replaced by an aspartic acid (D). 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	0.64
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.046
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;.
Vest4		0.70
MutPred		0.75		Gain of disorder (P = 0.0575);.;
MVP		0.14
MPC		0.35
ClinPred		0.96	D
GERP RS		2.8
Varity_R		0.77
gMVP		0.32

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: rs1576885548; hg19: chr3-182870242;