rs35079932

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001042545.2(LTBP4):c.3327G>A(p.Val1109Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,613,582 control chromosomes in the GnomAD database, including 2,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 126 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2276 hom. )

Consequence

LTBP4
NM_001042545.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.713

Publications

9 publications found

Variant links:

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

LTBP4 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=-0.76).

BP6

Variant 19-40622510-G-A is Benign according to our data. Variant chr19-40622510-G-A is described in ClinVar as Benign. ClinVar VariationId is 226722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.713 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LTBP4	NM_001042545.2 link	c.3327G>A	p.Val1109Val	synonymous_variant	Exon 23 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1 link	c.3528G>A	p.Val1176Val	synonymous_variant	Exon 26 of 33		NP_001036009.1
LTBP4	NM_003573.2 link	c.3417G>A	p.Val1139Val	synonymous_variant	Exon 26 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.3327G>A	p.Val1109Val	synonymous_variant	Exon 23 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5160

AN:

152260

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0555

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0390

AC:

9655

AN:

247548

AF XY:

0.0414

show subpopulations

Gnomad AFR exome

AF:

0.00866

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0647

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0562

Gnomad OTH exome

AF:

0.0438

GnomAD4 exome

AF:

0.0520

AC:

76015

AN:

1461204

Hom.:

2276

Cov.:

AF XY:

0.0521

AC XY:

37873

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.00819

AC:

274

AN:

33466

American (AMR)

AF:

0.0186

AC:

833

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0619

AC:

1615

AN:

26098

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.0445

AC:

3837

AN:

86232

European-Finnish (FIN)

AF:

0.0175

AC:

933

AN:

53300

Middle Eastern (MID)

AF:

0.0539

AC:

309

AN:

5730

European-Non Finnish (NFE)

AF:

0.0589

AC:

65444

AN:

1111684

Other (OTH)

AF:

0.0458

AC:

2765

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

4465

8930

13394

17859

22324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2416

4832

7248

9664

12080

<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:

0.0338

AC:

5156

AN:

152378

Hom.:

126

Cov.:

AF XY:

0.0319

AC XY:

2377

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00969

AC:

403

AN:

41590

American (AMR)

AF:

0.0210

AC:

321

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0416

AC:

201

AN:

4830

European-Finnish (FIN)

AF:

0.0158

AC:

168

AN:

10630

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0555

AC:

3774

AN:

68038

Other (OTH)

AF:

0.0355

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

255

509

764

1018

1273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0496

Hom.:

695

Bravo

AF:

0.0330

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0574

EpiControl

AF:

0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val1176Val in exon 26 of LTBP4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 5.4% (442/8252) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35079932). -

Oct 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

LTBP4-related disorder

Benign:1

Apr 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.7

(source)

DANN

Benign

0.69

PhyloP100

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over