NM_001042545.2:c.2053G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001042545.2(LTBP4):c.2053G>A(p.Asp685Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0101 in 1,603,676 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D685G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 11 hom., cov: 32)

Exomes 𝑓: 0.010 ( 119 hom. )

Consequence

LTBP4
NM_001042545.2 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.62

Publications

18 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 -16 ACMG points.

BP6

Variant 19-40611394-G-A is Benign according to our data. Variant chr19-40611394-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386527.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 = 0.00732 (1115/152356) while in subpopulation NFE AF = 0.0109 (744/68034). AF 95% confidence interval is 0.0103. There are 11 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.2053G>A	p.Asp685Asn	missense_variant, splice_region_variant	Exon 13 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.2254G>A	p.Asp752Asn	missense_variant, splice_region_variant	Exon 16 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.2143G>A	p.Asp715Asn	missense_variant, splice_region_variant	Exon 16 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.2053G>A	p.Asp685Asn	missense_variant, splice_region_variant	Exon 13 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1115

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00769

AC:

1838

AN:

239032

AF XY:

0.00781

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.000409

Gnomad EAS exome

AF:

0.0000563

Gnomad FIN exome

AF:

0.0228

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.00423

GnomAD4 exome

AF:

0.0103

AC:

15013

AN:

1451320

Hom.:

119

Cov.:

AF XY:

0.0101

AC XY:

7322

AN XY:

721674

show subpopulations

African (AFR)

AF:

0.000932

AC:

AN:

33268

American (AMR)

AF:

0.00114

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00204

AC:

175

AN:

85946

European-Finnish (FIN)

AF:

0.0208

AC:

1009

AN:

48528

Middle Eastern (MID)

AF:

0.000239

AC:

AN:

4180

European-Non Finnish (NFE)

AF:

0.0120

AC:

13345

AN:

1109212

Other (OTH)

AF:

0.00660

AC:

396

AN:

60016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

816

1633

2449

3266

4082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.00732

AC:

1115

AN:

152356

Hom.:

Cov.:

AF XY:

0.00801

AC XY:

597

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41588

American (AMR)

AF:

0.00124

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0250

AC:

266

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

744

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00997

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00264

AC:

ESP6500EA

AF:

0.00782

AC:

ExAC

AF:

0.00813

AC:

980

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00845

EpiControl

AF:

0.00824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30804560) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LTBP4: BS1, BS2 -

not specified

Benign:2

Jun 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp752Asn in exon 16 of LTBP4: This variant is not expected to have clinical s ignificance because it has been identified in 2.3% (150/6532) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs34093919). -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.65

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.0092

T;T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.8

.;M;.

PhyloP100

4.6

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.62

Sift

Benign

0.054

T;D;T

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.50

.;P;.

Vest4

0.56

MVP

0.76

MPC

0.95

ClinPred

0.035

GERP RS

3.9

Varity_R

0.22

gMVP

0.84

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: 0

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