Genetic Variant LTBP3:p.Leu35dup (chr11-65557854-C-CCAG) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001130144.3(LTBP3):c.103_105dupCTG(p.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 0.0213 in 1,302,838 control chromosomes in the GnomAD database, including 113 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 32 hom., cov: 27)

Exomes 𝑓: 0.022 ( 81 hom. )

Consequence

LTBP3
NM_001130144.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001130144.3

BP6

Variant 11-65557854-C-CCAG is Benign according to our data. Variant chr11-65557854-C-CCAG is described in ClinVar as Benign. ClinVar VariationId is 464024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.019 (2833/149228) while in subpopulation AFR AF = 0.0245 (1005/41026). AF 95% confidence interval is 0.0232. There are 32 homozygotes in GnomAd4. There are 1303 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 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.103_105dupCTG	p.Leu35dup	conservative_inframe_insertion	Exon 1 of 28	NP_001123616.1
LTBP3	NM_021070.4		c.103_105dupCTG	p.Leu35dup	conservative_inframe_insertion	Exon 1 of 27	NP_066548.2
LTBP3	NM_001164266.1		c.-245_-243dupCTG		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.103_105dupCTG	p.Leu35dup	conservative_inframe_insertion	Exon 1 of 28	ENSP00000301873.5
LTBP3	ENST00000322147.8	TSL:1	c.103_105dupCTG	p.Leu35dup	conservative_inframe_insertion	Exon 1 of 27	ENSP00000326647.4
LTBP3	ENST00000528516.5	TSL:1	n.103_105dupCTG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2828

AN:

149138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00661

Gnomad AMR

AF:

0.0176

Gnomad ASJ

AF:

0.00526

Gnomad EAS

AF:

0.00332

Gnomad SAS

AF:

0.00564

Gnomad FIN

AF:

0.00589

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.0280

GnomAD2 exomes

AF:

0.0509

AC:

1681

AN:

33030

AF XY:

0.0506

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.0557

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.0121

Gnomad FIN exome

AF:

0.0327

Gnomad NFE exome

AF:

0.0596

Gnomad OTH exome

AF:

0.0723

GnomAD4 exome

AF:

0.0215

AC:

24860

AN:

1153610

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

12032

AN XY:

563686

show subpopulations

African (AFR)

AF:

0.0227

AC:

544

AN:

23940

American (AMR)

AF:

0.0183

AC:

349

AN:

19050

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

131

AN:

17500

East Asian (EAS)

AF:

0.00603

AC:

153

AN:

25370

South Asian (SAS)

AF:

0.00733

AC:

350

AN:

47758

European-Finnish (FIN)

AF:

0.00663

AC:

174

AN:

26232

Middle Eastern (MID)

AF:

0.0176

AC:

AN:

3748

European-Non Finnish (NFE)

AF:

0.0235

AC:

22210

AN:

943690

Other (OTH)

AF:

0.0191

AC:

883

AN:

46322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

930

1859

2789

3718

4648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

944

1888

2832

3776

4720

<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:

0.0190

AC:

2833

AN:

149228

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1303

AN XY:

72828

show subpopulations

African (AFR)

AF:

0.0245

AC:

1005

AN:

41026

American (AMR)

AF:

0.0175

AC:

264

AN:

15044

Ashkenazi Jewish (ASJ)

AF:

0.00526

AC:

AN:

3424

East Asian (EAS)

AF:

0.00333

AC:

AN:

5110

South Asian (SAS)

AF:

0.00565

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00589

AC:

AN:

9682

Middle Eastern (MID)

AF:

0.00699

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0206

AC:

1380

AN:

66912

Other (OTH)

AF:

0.0277

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

280

420

560

700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00192

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Brachyolmia-amelogenesis imperfecta syndrome (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-CCAGCAGCAGCAGCAGCAGCAGCAG

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