19-40613923-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001042545.2(LTBP4):c.2565C>T(p.Asp855Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,613,452 control chromosomes in the GnomAD database, including 6,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 497 hom., cov: 31)

Exomes 𝑓: 0.086 ( 5910 hom. )

Consequence

LTBP4
NM_001042545.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.331

Publications

16 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 19-40613923-C-T is Benign according to our data. Variant chr19-40613923-C-T is described in ClinVar as Benign. ClinVar VariationId is 163947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.331 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LTBP4	NM_001042545.2 link	c.2565C>T	p.Asp855Asp	synonymous_variant	Exon 18 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1 link	c.2766C>T	p.Asp922Asp	synonymous_variant	Exon 21 of 33		NP_001036009.1
LTBP4	NM_003573.2 link	c.2655C>T	p.Asp885Asp	synonymous_variant	Exon 21 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.2565C>T	p.Asp855Asp	synonymous_variant	Exon 18 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes

AF:

0.0738

AC:

11206

AN:

151930

Hom.:

497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0268

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.0560

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.00310

Gnomad SAS

AF:

0.0519

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.119

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0776

GnomAD2 exomes

AF:

0.0784

AC:

19455

AN:

248080

AF XY:

0.0803

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0460

Gnomad ASJ exome

AF:

0.129

Gnomad EAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.0929

GnomAD4 exome

AF:

0.0865

AC:

126351

AN:

1461404

Hom.:

5910

Cov.:

AF XY:

0.0867

AC XY:

63020

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.0242

AC:

810

AN:

33476

American (AMR)

AF:

0.0492

AC:

2199

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3399

AN:

26122

East Asian (EAS)

AF:

0.00144

AC:

AN:

39698

South Asian (SAS)

AF:

0.0598

AC:

5158

AN:

86246

European-Finnish (FIN)

AF:

0.114

AC:

6086

AN:

53264

Middle Eastern (MID)

AF:

0.120

AC:

692

AN:

5768

European-Non Finnish (NFE)

AF:

0.0924

AC:

102770

AN:

1111754

Other (OTH)

AF:

0.0858

AC:

5180

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

7233

14466

21700

28933

36166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3504

7008

10512

14016

17520

<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:

0.0737

AC:

11204

AN:

152048

Hom.:

497

Cov.:

AF XY:

0.0736

AC XY:

5472

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0268

AC:

1110

AN:

41492

American (AMR)

AF:

0.0559

AC:

854

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

442

AN:

3470

East Asian (EAS)

AF:

0.00291

AC:

AN:

5156

South Asian (SAS)

AF:

0.0519

AC:

250

AN:

4816

European-Finnish (FIN)

AF:

0.113

AC:

1192

AN:

10592

Middle Eastern (MID)

AF:

0.117

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.103

AC:

7004

AN:

67936

Other (OTH)

AF:

0.0768

AC:

162

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

529

1059

1588

2118

2647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0840

Hom.:

511

Bravo

AF:

0.0674

Asia WGS

AF:

0.0400

AC:

138

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.106

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

Asp922Asp in exon 21 of LTBP4: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.0% (840/8402) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2077407). -

Oct 10, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

-0.33

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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