19-40610549-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042545.2(LTBP4):c.1702C>G(p.Arg568Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 1,593,254 control chromosomes in the GnomAD database, including 1,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R568P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 82 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1576 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.126

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003421694).

BP6

Variant 19-40610549-C-G is Benign according to our data. Variant chr19-40610549-C-G is described in ClinVar as [Benign]. Clinvar id is 329310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0288 (4385/152318) while in subpopulation NFE AF = 0.0456 (3105/68032). AF 95% confidence interval is 0.0443. There are 82 homozygotes in GnomAd4. There are 2005 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 82 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.1702C>G	p.Arg568Gly	missense_variant	Exon 12 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.1903C>G	p.Arg635Gly	missense_variant	Exon 15 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.1792C>G	p.Arg598Gly	missense_variant	Exon 15 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.1702C>G	p.Arg568Gly	missense_variant	Exon 12 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4387

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00806

Gnomad FIN

AF:

0.0395

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0457

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0275

AC:

5921

AN:

215696

AF XY:

0.0277

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0229

Gnomad EAS exome

AF:

0.0000593

Gnomad FIN exome

AF:

0.0408

Gnomad NFE exome

AF:

0.0429

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0431

AC:

62133

AN:

1440936

Hom.:

1576

Cov.:

AF XY:

0.0421

AC XY:

30184

AN XY:

716438

show subpopulations

African (AFR)

AF:

0.00719

AC:

240

AN:

33370

American (AMR)

AF:

0.0143

AC:

619

AN:

43168

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

587

AN:

25904

East Asian (EAS)

AF:

0.000102

AC:

AN:

39402

South Asian (SAS)

AF:

0.0116

AC:

984

AN:

84800

European-Finnish (FIN)

AF:

0.0436

AC:

1791

AN:

41084

Middle Eastern (MID)

AF:

0.00729

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0503

AC:

55746

AN:

1107546

Other (OTH)

AF:

0.0354

AC:

2120

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3250

6499

9749

12998

16248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0288

AC:

4385

AN:

152318

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2005

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00861

AC:

358

AN:

41568

American (AMR)

AF:

0.0219

AC:

335

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00807

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0395

AC:

419

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0456

AC:

3105

AN:

68032

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

237

474

712

949

1186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0311

Hom.:

Bravo

AF:

0.0273

TwinsUK

AF:

0.0547

AC:

203

ALSPAC

AF:

0.0527

AC:

203

ESP6500AA

AF:

0.00630

AC:

ESP6500EA

AF:

0.0420

AC:

351

ExAC

AF:

0.0254

AC:

3060

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

Arg635Gly in exon 15 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 4.2% (351/8364) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs33937741). -

Sep 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LTBP4-related disorder

Benign:1

Apr 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.17

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.43

.;N;.

PhyloP100

0.13

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.28

T;T;T

Polyphen

0.83

.;P;.

Vest4

0.47

MPC

1.0

ClinPred

0.042

GERP RS

2.8

Varity_R

0.27

gMVP

0.60

Mutation Taster

=93/7

polymorphism (auto)

(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

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19-40610549-C-G

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