chr11-65557854-C-CCAGCAGCAG

Position:

• chr11-65557854-C-CCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001130144.3(LTBP3):​c.97_105dupCTGCTGCTG​(p.Leu33_Leu35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,320,230 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: LTBP3 NM_001130144.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.342

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 11-65557854-C-CCAGCAGCAG is Benign according to our data. Variant chr11-65557854-C-CCAGCAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464029.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (339/149252) while in subpopulation NFE AF= 0.00347 (232/66922). AF 95% confidence interval is 0.0031. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP3	NM_001130144.3	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	1/28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	1/27		NP_066548.2
LTBP3	NM_001164266.1	c.-251_-243dupCTGCTGCTG		5_prime_UTR_variant	1/27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	1/28	2	NM_001130144.3	ENSP00000301873.5

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 339 AN: 149162 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000929

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00260

Gnomad ASJ AF: 0.00467

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.000206

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.000982

GnomAD3 exomes AF: 0.00182 AC: 60 AN: 33030 Hom.: 0 AF XY: 0.00172 AC XY: 33 AN XY: 19164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000741

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00297 AC: 3478 AN: 1170978 Hom.: 8 Cov.: 26 AF XY: 0.00294 AC XY: 1682 AN XY: 572164

Gnomad4 AFR exome AF: 0.000751

Gnomad4 AMR exome AF: 0.00375

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.00102

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00227 AC: 339 AN: 149252 Hom.: 0 Cov.: 27 AF XY: 0.00207 AC XY: 151 AN XY: 72844

Gnomad4 AFR AF: 0.000926

Gnomad4 AMR AF: 0.00259

Gnomad4 ASJ AF: 0.00467

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000206

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.000973

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

Brachyolmia-amelogenesis imperfecta syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

LTBP3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71036212; hg19: chr11-65325325;