11-65552397-G-T

Variant names:

• chr11-65552397-G-T
• rs764981765
• NM_001130144.3:c.1196C>A

Variant summary

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

The NM_001130144.3(LTBP3):​c.1196C>A​(p.Pro399Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P399L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.29
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Acromicric dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302197 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	NM_001130144.3	MANE Select	c.1196C>A	p.Pro399Gln	missense	Exon 7 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.1196C>A	p.Pro399Gln	missense	Exon 7 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.845C>A	p.Pro282Gln	missense	Exon 7 of 27	NP_001157738.1	Q9NS15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.1196C>A	p.Pro399Gln	missense	Exon 7 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.1196C>A	p.Pro399Gln	missense	Exon 7 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*841C>A		non_coding_transcript_exon	Exon 7 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.42		Gain of methylation at K398 (P = 0.0835)
MVP		0.86
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.79
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764981765; hg19: chr11-65319868;