rs145001056

chr11-65551473-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001130144.3(LTBP3):c.1550C>T(p.Pro517Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P517P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: LTBP3 NM_001130144.3 missense, splice_region
• Scores: Splicing: ADA: 0.6580
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 2.38

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02069956).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000248 (362/1461800) while in subpopulation SAS AF= 0.00172 (148/86258). AF 95% confidence interval is 0.00149. There are 1 homozygotes in gnomad4_exome. There are 227 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP3	NM_001130144.3	c.1550C>T	p.Pro517Leu	missense_variant, splice_region_variant	10/28	ENST00000301873.11
LTBP3	NM_021070.4	c.1550C>T	p.Pro517Leu	missense_variant, splice_region_variant	10/27
LTBP3	NM_001164266.1	c.1199C>T	p.Pro400Leu	missense_variant, splice_region_variant	10/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP3	ENST00000301873.11	c.1550C>T	p.Pro517Leu	missense_variant, splice_region_variant	10/28	2	NM_001130144.3	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 250790 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461800 Hom.: 1 Cov.: 33 AF XY: 0.000312 AC XY: 227 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74434

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2017	The P517L variant in the LTBP3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P517L variant is observed in 27/16444 (0.16%) alleles from individuals of South Asian background and 9/66050 (0.013%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P517L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P517L as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2016	- -

Brachyolmia-amelogenesis imperfecta syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 517 of the LTBP3 protein (p.Pro517Leu). This variant is present in population databases (rs145001056, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of LTBP3-related conditions (PMID: 29625025). ClinVar contains an entry for this variant (Variation ID: 235669). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;N;D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.11	B;B;P
Vest4		0.60
MVP		0.71
ClinPred		0.077	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Benign	0.63
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: rs145001056; hg19: chr11-65318944;