11-65557854-CCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAG

Variant names:

• chr11-65557854-CCAGCAG-C
• rs71036212
• NM_001130144.3:c.100_105delCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001130144.3(LTBP3):​c.100_105delCTGCTG​(p.Leu34_Leu35del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,319,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.420
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001130144.3

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.100_105delCTGCTG	p.Leu34_Leu35del	conservative_inframe_deletion	Exon 1 of 28	NP_001123616.1
	LTBP3	NM_021070.4		c.100_105delCTGCTG	p.Leu34_Leu35del	conservative_inframe_deletion	Exon 1 of 27	NP_066548.2
	LTBP3	NM_001164266.1		c.-248_-243delCTGCTG		5_prime_UTR	Exon 1 of 27	NP_001157738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.100_105delCTGCTG	p.Leu34_Leu35del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000301873.5
	LTBP3	ENST00000322147.8	TSL:1	c.100_105delCTGCTG	p.Leu34_Leu35del	conservative_inframe_deletion	Exon 1 of 27	ENSP00000326647.4
	LTBP3	ENST00000528516.5	TSL:1	n.100_105delCTGCTG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes AF: 0.0000939 AC: 14 AN: 149158 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000780

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000747

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 188 AN: 1169818 Hom.: 0 AF XY: 0.000187 AC XY: 107 AN XY: 571532

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

African (AFR) AF: 0.000167 AC: 4 AN: 23952

American (AMR) AF: 0.000471 AC: 9 AN: 19102

Ashkenazi Jewish (ASJ) AF: 0.000226 AC: 4 AN: 17662

East Asian (EAS) AF: 0.000511 AC: 13 AN: 25420

South Asian (SAS) AF: 0.000627 AC: 30 AN: 47834

European-Finnish (FIN) AF: 0.000151 AC: 4 AN: 26408

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3816

European-Non Finnish (NFE) AF: 0.000117 AC: 112 AN: 958804

Other (OTH) AF: 0.000235 AC: 11 AN: 46820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000938 AC: 14 AN: 149248 Hom.: 0 Cov.: 27 AF XY: 0.0000824 AC XY: 6 AN XY: 72844

African (AFR) AF: 0.0000731 AC: 3 AN: 41032

American (AMR) AF: 0.0000665 AC: 1 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.000103 AC: 1 AN: 9684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000747 AC: 5 AN: 66920

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 40

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	1	-	LTBP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=187/13	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71036212; hg19: chr11-65325325;