rs752375653

chr11-65546811-GC-Gchr11-65546811-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001130144.3(LTBP3):c.2216del(p.Gly739AlafsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,537,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.99

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-65546811-GC-G is Pathogenic according to our data. Variant chr11-65546811-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 204496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP3	NM_001130144.3	c.2216del	p.Gly739AlafsTer7	frameshift_variant	15/28	ENST00000301873.11
LTBP3	NM_021070.4	c.2216del	p.Gly739AlafsTer7	frameshift_variant	15/27
LTBP3	NM_001164266.1	c.1865del	p.Gly622AlafsTer7	frameshift_variant	15/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP3	ENST00000301873.11	c.2216del	p.Gly739AlafsTer7	frameshift_variant	15/28	2	NM_001130144.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 4 AN: 146426 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000451

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000294 AC: 7 AN: 238376 Hom.: 0 AF XY: 0.0000306 AC XY: 4 AN XY: 130688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000180 AC: 25 AN: 1391344 Hom.: 0 Cov.: 36 AF XY: 0.0000130 AC XY: 9 AN XY: 691906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000776

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.0000536

GnomAD4 genome AF: 0.0000273 AC: 4 AN: 146426 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000215

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000451

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with LTBP3 -related disorder (ClinVar ID: VCV000204496 / PMID: 25669657). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Institute of Human Genetics, University of Ulm	Nov 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752375653; hg19: chr11-65314282;