NM_001042545.2:c.379G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042545.2(LTBP4):c.379G>A(p.Val127Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,609,426 control chromosomes in the GnomAD database, including 171,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 20449 hom., cov: 32)

Exomes 𝑓: 0.45 ( 150971 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.185

Publications

64 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=1.2299933E-5).

BP6

Variant 19-40605163-G-A is Benign according to our data. Variant chr19-40605163-G-A is described in ClinVar as Benign. ClinVar VariationId is 163945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.379G>A	p.Val127Ile	missense_variant	Exon 2 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.580G>A	p.Val194Ile	missense_variant	Exon 5 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.469G>A	p.Val157Ile	missense_variant	Exon 5 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.379G>A	p.Val127Ile	missense_variant	Exon 2 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

76876

AN:

151908

Hom.:

20415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.381

Gnomad ASJ

AF:

0.583

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.552

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.461

AC:

110943

AN:

240400

AF XY:

0.468

show subpopulations

Gnomad AFR exome

AF:

0.671

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.581

Gnomad EAS exome

AF:

0.419

Gnomad FIN exome

AF:

0.483

Gnomad NFE exome

AF:

0.445

Gnomad OTH exome

AF:

0.453

GnomAD4 exome

AF:

0.451

AC:

657856

AN:

1457400

Hom.:

150971

Cov.:

AF XY:

0.456

AC XY:

330487

AN XY:

724720

show subpopulations

African (AFR)

AF:

0.678

AC:

22662

AN:

33412

American (AMR)

AF:

0.319

AC:

14041

AN:

44016

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

14975

AN:

26032

East Asian (EAS)

AF:

0.371

AC:

14651

AN:

39528

South Asian (SAS)

AF:

0.557

AC:

47734

AN:

85720

European-Finnish (FIN)

AF:

0.486

AC:

25607

AN:

52710

Middle Eastern (MID)

AF:

0.503

AC:

2895

AN:

5756

European-Non Finnish (NFE)

AF:

0.438

AC:

486524

AN:

1110032

Other (OTH)

AF:

0.478

AC:

28767

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

21447

42893

64340

85786

107233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14774

29548

44322

59096

73870

<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:

0.506

AC:

76965

AN:

152026

Hom.:

20449

Cov.:

AF XY:

0.506

AC XY:

37592

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.664

AC:

27548

AN:

41482

American (AMR)

AF:

0.381

AC:

5822

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.583

AC:

2024

AN:

3470

East Asian (EAS)

AF:

0.402

AC:

2074

AN:

5164

South Asian (SAS)

AF:

0.554

AC:

2667

AN:

4816

European-Finnish (FIN)

AF:

0.495

AC:

5227

AN:

10564

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30122

AN:

67940

Other (OTH)

AF:

0.472

AC:

993

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1890

3779

5669

7558

9448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.457

Hom.:

56812

Bravo

AF:

0.502

TwinsUK

AF:

0.442

AC:

1638

ALSPAC

AF:

0.436

AC:

1682

ESP6500AA

AF:

0.660

AC:

2543

ESP6500EA

AF:

0.454

AC:

3739

ExAC

AF:

0.465

AC:

56062

Asia WGS

AF:

0.495

AC:

1722

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Benign:4

Jan 12, 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. -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val194Ile in exon 5 of LTBP4: This variant is not expected to have clinical sign ificance because it has been identified in 45.4% (3739/8234) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2303729). -

Sep 29, 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. -

Jul 22, 2015

Eurofins Ntd Llc (ga)

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

T;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.18

T;T;T

MetaRNN

Benign

0.000012

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

.;N;.

PhyloP100

-0.18

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.046

MPC

0.66

ClinPred

0.0061

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.063

Mutation Taster

=98/2

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