rs7367

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.3687C>T(p.Asp1229Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,613,160 control chromosomes in the GnomAD database, including 144,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 20872 hom., cov: 32)

Exomes 𝑓: 0.40 ( 123676 hom. )

Consequence

LTBP4
NM_001042545.2 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.517

Publications

24 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=-0.65).

BP6

Variant 19-40623937-C-T is Benign according to our data. Variant chr19-40623937-C-T is described in ClinVar as Benign. ClinVar VariationId is 163950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.517 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.3687C>T	p.Asp1229Asp	splice_region_variant, synonymous_variant	Exon 26 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.3888C>T	p.Asp1296Asp	splice_region_variant, synonymous_variant	Exon 29 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.3777C>T	p.Asp1259Asp	splice_region_variant, synonymous_variant	Exon 29 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.3687C>T	p.Asp1229Asp	splice_region_variant, synonymous_variant	Exon 26 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.497

AC:

75512

AN:

152018

Hom.:

20830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.741

Gnomad AMI

AF:

0.287

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.503

Gnomad MID

AF:

0.478

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.459

GnomAD2 exomes

AF:

0.430

AC:

106381

AN:

247670

AF XY:

0.433

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.374

Gnomad FIN exome

AF:

0.488

Gnomad NFE exome

AF:

0.389

Gnomad OTH exome

AF:

0.418

GnomAD4 exome

AF:

0.404

AC:

590242

AN:

1461024

Hom.:

123676

Cov.:

AF XY:

0.408

AC XY:

296745

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.763

AC:

25548

AN:

33472

American (AMR)

AF:

0.306

AC:

13646

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14344

AN:

26106

East Asian (EAS)

AF:

0.322

AC:

12777

AN:

39688

South Asian (SAS)

AF:

0.521

AC:

44940

AN:

86214

European-Finnish (FIN)

AF:

0.485

AC:

25857

AN:

53362

Middle Eastern (MID)

AF:

0.466

AC:

2687

AN:

5764

European-Non Finnish (NFE)

AF:

0.381

AC:

423986

AN:

1111436

Other (OTH)

AF:

0.439

AC:

26457

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

18323

36646

54968

73291

91614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13438

26876

40314

53752

67190

<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:

0.497

AC:

75612

AN:

152136

Hom.:

20872

Cov.:

AF XY:

0.499

AC XY:

37159

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.742

AC:

30795

AN:

41502

American (AMR)

AF:

0.366

AC:

5598

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

1929

AN:

3472

East Asian (EAS)

AF:

0.352

AC:

1816

AN:

5162

South Asian (SAS)

AF:

0.523

AC:

2523

AN:

4828

European-Finnish (FIN)

AF:

0.503

AC:

5326

AN:

10580

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26262

AN:

67978

Other (OTH)

AF:

0.456

AC:

964

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1796

3592

5388

7184

8980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.422

Hom.:

32363

Bravo

AF:

0.494

Asia WGS

AF:

0.458

AC:

1590

AN:

3478

EpiCase

AF:

0.399

EpiControl

AF:

0.394

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Asp1296Asp in exon 29 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 40.0% (3347/8358) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7367). -

Sep 29, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=71/29

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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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