11-65539085-G-T

Position:

• chr11-65539085-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130144.3(LTBP3):​c.3907C>A​(p.Arg1303Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000798 in 1,253,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.58

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38416794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP3	NM_001130144.3	c.3907C>A	p.Arg1303Ser	missense_variant	28/28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4	c.3766C>A	p.Arg1256Ser	missense_variant	27/27		NP_066548.2
LTBP3	NM_001164266.1	c.3415C>A	p.Arg1139Ser	missense_variant	27/27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11	c.3907C>A	p.Arg1303Ser	missense_variant	28/28	2	NM_001130144.3	ENSP00000301873	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.98e-7 AC: 1 AN: 1253072 Hom.: 0 Cov.: 31 AF XY: 0.00000163 AC XY: 1 AN XY: 612142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000197

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2021

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LTBP3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1303 of the LTBP3 protein (p.Arg1303Ser). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The p.R1303S variant (also known as c.3907C>A), located in coding exon 28 of the LTBP3 gene, results from a C to A substitution at nucleotide position 3907. The arginine at codon 1303 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.5	.;L;.;.;.
MutationTaster	Benign	0.90	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.96	N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;P;.;.;D
Vest4		0.42
MutPred		0.50		.;Gain of phosphorylation at R1303 (P = 0.0051);.;.;.;
MVP		0.68
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.24
gMVP		0.45

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: rs1186461257; hg19: chr11-65306556;