11-65557827-GC-G

Variant names:

• chr11-65557827-GC-G
• rs1286042594
• NM_001130144.3:c.132delG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001130144.3(LTBP3):​c.132delG​(p.Pro45ArgfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,462,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G44G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: -0.138
• Publications: 5 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-65557827-GC-G is Pathogenic according to our data. Variant chr11-65557827-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 523637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	NM_001130144.3	MANE Select	c.132delG	p.Pro45ArgfsTer25	frameshift	Exon 1 of 28	NP_001123616.1
	LTBP3	NM_021070.4		c.132delG	p.Pro45ArgfsTer25	frameshift	Exon 1 of 27	NP_066548.2
	LTBP3	NM_001164266.1		c.-216delG		5_prime_UTR	Exon 1 of 27	NP_001157738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.132delG	p.Pro45ArgfsTer25	frameshift	Exon 1 of 28	ENSP00000301873.5
	LTBP3	ENST00000322147.8	TSL:1	c.132delG	p.Pro45ArgfsTer25	frameshift	Exon 1 of 27	ENSP00000326647.4
	LTBP3	ENST00000528516.5	TSL:1	n.132delG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 150968 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000474 AC: 4 AN: 84462 AF XY: 0.0000632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000186

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000181

Gnomad NFE exome AF: 0.0000297

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 6 AN: 1311052 Hom.: 0 Cov.: 31 AF XY: 0.00000619 AC XY: 4 AN XY: 646290

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27360

American (AMR) AF: 0.00 AC: 0 AN: 28096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21694

East Asian (EAS) AF: 0.00 AC: 0 AN: 30794

South Asian (SAS) AF: 0.0000285 AC: 2 AN: 70190

European-Finnish (FIN) AF: 0.0000604 AC: 2 AN: 33122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5130

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1040468

Other (OTH) AF: 0.00 AC: 0 AN: 54198

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0220673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 150968 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73704

African (AFR) AF: 0.0000485 AC: 2 AN: 41220

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67636

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Pathogenic:3

May 11, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift: 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 (PVS1_VS). The variant has been reported to be associated with LTBP3 related disorder (ClinVar ID: VCV000523637, PMID:29625025). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000047, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Nov 17, 2020

Institute of Human Genetics, University of Ulm

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:1

Dec 19, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heritable Thoracic Aortic Disease Other:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: confers sensitivity

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1286042594; hg19: chr11-65325298;