NM_014398.4:c.747A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014398.4(LAMP3):c.747A>C(p.Gln249His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

LAMP3
NM_014398.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.312

Publications

0 publications found

Variant links:

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]

LAMP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34722632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP3	NM_014398.4 link	c.747A>C	p.Gln249His	missense_variant	Exon 2 of 6	ENST00000265598.8	NP_055213.2	Q9UQV4
LAMP3	XM_005247360.6 link	c.747A>C	p.Gln249His	missense_variant	Exon 3 of 7		XP_005247417.1
LAMP3	XM_047447967.1 link	c.747A>C	p.Gln249His	missense_variant	Exon 2 of 6		XP_047303923.1
LAMP3	XM_011512688.3 link	c.747A>C	p.Gln249His	missense_variant	Exon 2 of 6		XP_011510990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMP3	ENST00000265598.8 link	c.747A>C	p.Gln249His	missense_variant	Exon 2 of 6	1	NM_014398.4	ENSP00000265598.3	Q9UQV4
LAMP3	ENST00000466939.1 link	c.675A>C	p.Gln225His	missense_variant	Exon 2 of 6	2		ENSP00000418912.1	E7ETP9
LAMP3	ENST00000476015.1 link	c.*207A>C		downstream_gene_variant		4		ENSP00000419059.1	C9JYP5
LAMP3	ENST00000470251.1 link	c.*246A>C		downstream_gene_variant		2		ENSP00000420589.1	C9JDI8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.33e-7

AC:

AN:

1364930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668412

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000331

AC:

AN:

30190

American (AMR)

AF:

0.00

AC:

AN:

28774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19874

East Asian (EAS)

AF:

0.00

AC:

AN:

38850

South Asian (SAS)

AF:

0.00

AC:

AN:

70024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065878

Other (OTH)

AF:

0.00

AC:

AN:

56146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 04, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.747A>C (p.Q249H) alteration is located in exon 2 (coding exon 2) of the LAMP3 gene. This alteration results from a A to C substitution at nucleotide position 747, causing the glutamine (Q) at amino acid position 249 to be replaced by a histidine (H). 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

0.27

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

0.029

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

0.31

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.15

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.28

MutPred

0.67

Gain of methylation at K251 (P = 0.1049);.;

MVP

0.18

MPC

0.39

ClinPred

0.90

GERP RS

-1.3

Varity_R

0.41

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

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

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NM_014398.4:c.747A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over