Genetic Variant LTBP3:p.Leu33_Leu35dup (chr11-65557854-C-CCAGCAGCAG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.342

Publications

4 publications found

Variant links:

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

LTBP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001130144.3

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 VariationId is 464029.

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 the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LTBP3	NM_001130144.3	MANE Select	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	NP_001123616.1
LTBP3	NM_021070.4		c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	NP_066548.2
LTBP3	NM_001164266.1		c.-251_-243dupCTGCTGCTG		5_prime_UTR	Exon 1 of 27	NP_001157738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	ENSP00000301873.5
LTBP3	ENST00000322147.8	TSL:1	c.97_105dupCTGCTGCTG	p.Leu33_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	ENSP00000326647.4
LTBP3	ENST00000528516.5	TSL:1	n.97_105dupCTGCTGCTG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

339

AN:

149162

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00182

AC:

AN:

33030

AF XY:

0.00172

show subpopulations

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 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.:

Cov.:

AF XY:

0.00294

AC XY:

1682

AN XY:

572164

show subpopulations

African (AFR)

AF:

0.000751

AC:

AN:

23980

American (AMR)

AF:

0.00375

AC:

AN:

19206

Ashkenazi Jewish (ASJ)

AF:

0.00593

AC:

105

AN:

17700

East Asian (EAS)

AF:

0.00102

AC:

AN:

25430

South Asian (SAS)

AF:

0.00129

AC:

AN:

48006

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

26434

Middle Eastern (MID)

AF:

0.00471

AC:

AN:

3820

European-Non Finnish (NFE)

AF:

0.00317

AC:

3039

AN:

959530

Other (OTH)

AF:

0.00277

AC:

130

AN:

46872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00227

AC:

339

AN:

149252

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

151

AN XY:

72844

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

41032

American (AMR)

AF:

0.00259

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00467

AC:

AN:

3424

East Asian (EAS)

AF:

0.000196

AC:

AN:

5110

South Asian (SAS)

AF:

0.00167

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

9686

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00347

AC:

232

AN:

66922

Other (OTH)

AF:

0.000973

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000274

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Brachyolmia-amelogenesis imperfecta syndrome (1)

Brachyolmia-amelogenesis imperfecta syndrome;C4540511:Geleophysic dysplasia 3 (1)

LTBP3-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.34

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Publications

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11-65557854-CCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over