Genetic Variant LTBP3:p.Pro517Arg (chr11-65551473-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001130144.3(LTBP3):c.1550C>G(p.Pro517Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P517L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

LTBP3
NM_001130144.3 missense, splice_region

Scores

Splicing: ADA: 0.7978

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.38

Publications

0 publications found

Variant links:

Genes affected

LTBP3 (HGNC:6716): (latent transforming growth factor beta binding protein 3) The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

LTBP3 Gene-Disease associations (from GenCC):

brachyolmia-amelogenesis imperfecta syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
geleophysic dysplasia 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Acromicric dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
geleophysic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LTBP3 links:

ENSG00000302197 (HGNC:):

ENSG00000302197 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-65551473-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235669.

BP4

Computational evidence support a benign effect (MetaRNN=0.26762268).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130144.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LTBP3	NM_001130144.3	MANE Select	c.1550C>G	p.Pro517Arg	missense splice_region	Exon 10 of 28	NP_001123616.1
LTBP3	NM_021070.4		c.1550C>G	p.Pro517Arg	missense splice_region	Exon 10 of 27	NP_066548.2
LTBP3	NM_001164266.1		c.1199C>G	p.Pro400Arg	missense splice_region	Exon 10 of 27	NP_001157738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.1550C>G	p.Pro517Arg	missense splice_region	Exon 10 of 28	ENSP00000301873.5
LTBP3	ENST00000322147.8	TSL:1	c.1550C>G	p.Pro517Arg	missense splice_region	Exon 10 of 27	ENSP00000326647.4
LTBP3	ENST00000528516.5	TSL:1	n.*1195C>G		splice_region non_coding_transcript_exon	Exon 10 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.012

Eigen_PC

Benign

0.093

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.0

PhyloP100

2.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Polyphen

0.61

Vest4

0.69

MutPred

0.34

Loss of glycosylation at T514 (P = 0.0398)

MVP

0.72

ClinPred

0.78

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.64

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.80

dbscSNV1_RF

Benign

0.56

SpliceAI score (max)

0.16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over