rs1554974135

Variant names:

• chr11-65547459-G-C
• rs1554974135
• NM_001130144.3:c.2087C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130144.3(LTBP3):​c.2087C>G​(p.Ser696Cys) variant causes a missense 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. 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. S696F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.184735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP3	NM_001130144.3	c.2087C>G	p.Ser696Cys	missense_variant	Exon 14 of 28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4	c.2087C>G	p.Ser696Cys	missense_variant	Exon 14 of 27		NP_066548.2
LTBP3	NM_001164266.1	c.1736C>G	p.Ser579Cys	missense_variant	Exon 14 of 27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11	c.2087C>G	p.Ser696Cys	missense_variant	Exon 14 of 28	2	NM_001130144.3	ENSP00000301873.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Geleophysic dysplasia 3 Pathogenic:1 Uncertain:1

Dec 13, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Uncertain Significance - Conflicting Evidence, for Geleophysic dysplasia 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/27068007). BS3-Supporting => BS3 downgraded in strength to supporting No effect on TGF-beta secretion (https://www.ncbi.nlm.nih.gov/pubmed/27068007). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;.;T;T
Eigen	Benign	0.073
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T;T;D;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	N;N;.;.;.
PhyloP100		2.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Benign	0.091	T;T;T;.;T
Polyphen		0.94	P;D;P;D;.
Vest4		0.58
MutPred		0.48		Loss of glycosylation at S696 (P = 0.0308);Loss of glycosylation at S696 (P = 0.0308);.;.;.;
MVP		0.28
ClinPred		0.68	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.84
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs1554974135; hg19: chr11-65314930;