11-65557854-CCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr11-65557854-C-CCAGCAGCAGCAG
• rs71036212
• NM_001130144.3:c.94_105dupCTGCTGCTGCTG

Variant summary

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

The NM_001130144.3(LTBP3):​c.94_105dupCTGCTGCTGCTG​(p.Leu32_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 0.000174 in 149,162 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LTBP3 NM_001130144.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.342
• 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.94_105dupCTGCTGCTGCTG	p.Leu32_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	NP_001123616.1
	LTBP3	NM_021070.4		c.94_105dupCTGCTGCTGCTG	p.Leu32_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	NP_066548.2
	LTBP3	NM_001164266.1		c.-254_-243dupCTGCTGCTGCTG		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.94_105dupCTGCTGCTGCTG	p.Leu32_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	ENSP00000301873.5
	LTBP3	ENST00000322147.8	TSL:1	c.94_105dupCTGCTGCTGCTG	p.Leu32_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	ENSP00000326647.4
	LTBP3	ENST00000528516.5	TSL:1	n.94_105dupCTGCTGCTGCTG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes AF: 0.000174 AC: 26 AN: 149162 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000329

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000908 AC: 3 AN: 33030 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000140 AC: 164 AN: 1171076 Hom.: 0 Cov.: 26 AF XY: 0.000147 AC XY: 84 AN XY: 572214

African (AFR) AF: 0.0000834 AC: 2 AN: 23982

American (AMR) AF: 0.000208 AC: 4 AN: 19206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17700

East Asian (EAS) AF: 0.0000393 AC: 1 AN: 25430

South Asian (SAS) AF: 0.000208 AC: 10 AN: 48008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3822

European-Non Finnish (NFE) AF: 0.000150 AC: 144 AN: 959616

Other (OTH) AF: 0.0000640 AC: 3 AN: 46878

GnomAD4 genome AF: 0.000174 AC: 26 AN: 149162 Hom.: 0 Cov.: 27 AF XY: 0.000165 AC XY: 12 AN XY: 72744

African (AFR) AF: 0.0000733 AC: 3 AN: 40926

American (AMR) AF: 0.00 AC: 0 AN: 15028

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

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000329 AC: 22 AN: 66932

Other (OTH) AF: 0.00 AC: 0 AN: 2036

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=84/16	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;