Genetic Variant LTBP3:p.Pro268Pro (chr11-65553761-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001130144.3(LTBP3):c.804C>T(p.Pro268Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,573,436 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 31)

Exomes 𝑓: 0.017 ( 267 hom. )

Consequence

LTBP3
NM_001130144.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.49

Publications

1 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:

ENSG00000302197 (HGNC:):

ENSG00000302197 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 11-65553761-G-A is Benign according to our data. Variant chr11-65553761-G-A is described in ClinVar as Benign. ClinVar VariationId is 464026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1805/151936) while in subpopulation NFE AF = 0.0183 (1243/67906). AF 95% confidence interval is 0.0175. There are 15 homozygotes in GnomAd4. There are 845 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 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.804C>T	p.Pro268Pro	synonymous	Exon 3 of 28	NP_001123616.1
LTBP3	NM_021070.4		c.804C>T	p.Pro268Pro	synonymous	Exon 3 of 27	NP_066548.2
LTBP3	NM_001164266.1		c.453C>T	p.Pro151Pro	synonymous	Exon 3 of 27	NP_001157738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.804C>T	p.Pro268Pro	synonymous	Exon 3 of 28	ENSP00000301873.5
LTBP3	ENST00000322147.8	TSL:1	c.804C>T	p.Pro268Pro	synonymous	Exon 3 of 27	ENSP00000326647.4
LTBP3	ENST00000528516.5	TSL:1	n.*449C>T		non_coding_transcript_exon	Exon 3 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1805

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00167

Gnomad FIN

AF:

0.0298

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.00815

GnomAD2 exomes

AF:

0.0127

AC:

2296

AN:

180764

AF XY:

0.0128

show subpopulations

Gnomad AFR exome

AF:

0.00352

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00583

Gnomad EAS exome

AF:

0.000740

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.0169

AC:

24016

AN:

1421500

Hom.:

267

Cov.:

AF XY:

0.0164

AC XY:

11580

AN XY:

704924

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33074

American (AMR)

AF:

0.00282

AC:

115

AN:

40820

Ashkenazi Jewish (ASJ)

AF:

0.00558

AC:

143

AN:

25630

East Asian (EAS)

AF:

0.000207

AC:

AN:

38570

South Asian (SAS)

AF:

0.00188

AC:

155

AN:

82662

European-Finnish (FIN)

AF:

0.0358

AC:

1295

AN:

36144

Middle Eastern (MID)

AF:

0.000875

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0196

AC:

21519

AN:

1099632

Other (OTH)

AF:

0.0116

AC:

689

AN:

59256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

1557

3113

4670

6226

7783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.0119

AC:

1805

AN:

151936

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

845

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.00364

AC:

151

AN:

41450

American (AMR)

AF:

0.00321

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3466

East Asian (EAS)

AF:

0.000195

AC:

AN:

5136

South Asian (SAS)

AF:

0.00167

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.0298

AC:

316

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1243

AN:

67906

Other (OTH)

AF:

0.00806

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

177

266

354

443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00753

Hom.:

Bravo

AF:

0.00986

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brachyolmia-amelogenesis imperfecta syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.72

(source)

DANN

Benign

0.89

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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