rs1220133830

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS1

The NM_001042545.2(LTBP4):c.56_67dupTAGGGCCGCAGC(p.Leu19_Gln22dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,458,068 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.150

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001042545.2.

BP6

Variant 19-40601436-G-GCGCAGCTAGGGC is Benign according to our data. Variant chr19-40601436-G-GCGCAGCTAGGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517252.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00025 (38/151842) while in subpopulation NFE AF = 0.000442 (30/67818). AF 95% confidence interval is 0.000318. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	Exon 1 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.451+1266_451+1277dupTAGGGCCGCAGC		intron_variant	Intron 4 of 32		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.340+1266_340+1277dupTAGGGCCGCAGC		intron_variant	Intron 4 of 32		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	Exon 1 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000572

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

78574

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000585

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

302

AN:

1306226

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

162

AN XY:

643488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26558

American (AMR)

AF:

0.00

AC:

AN:

26572

Ashkenazi Jewish (ASJ)

AF:

0.0000439

AC:

AN:

22802

East Asian (EAS)

AF:

0.00

AC:

AN:

28108

South Asian (SAS)

AF:

0.0000563

AC:

AN:

71016

European-Finnish (FIN)

AF:

0.000634

AC:

AN:

33132

Middle Eastern (MID)

AF:

0.000229

AC:

AN:

4358

European-Non Finnish (NFE)

AF:

0.000259

AC:

269

AN:

1039812

Other (OTH)

AF:

0.000111

AC:

AN:

53868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000250

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41508

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000572

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000442

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.547

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.000128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jan 16, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LTBP4 (NM_003573.2) c.340+1266_340+1277dup12 is located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. In addition, the variant is located to the first exon of an alternative transcript, where it is predicted to result in an in-frame duplication change (i.e. NM_001042545.2 c.56_67dup p.(Leu19_Gln22dup)). The variant allele was found at a frequency of 0.00023 in 1,452,510 control chromosomes, predominantly at a frequency of 0.00062 within the Finnish subpopulation in the gnomAD database (v4 dataset). However in certain European subpopulations the variant is reported with even higher allele frequencies, e.g. in the Estonians (i.e. 8/4648 alleles; AF: 0.001721), suggesting that the variant is likely a benign polymorphism. To our knowledge, no occurrence of c.340+1266_340+1277dup12 in individuals affected with Cutis Laxa - LTBP4 Related and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 517252). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Leu19_Gln22dup variant in LTBP4 has not been previously reported in indivi duals with pulmonary disease. Data from large population studies is insufficient to assess the frequency of this variant. This variant is a duplication of 4 ami no acids at positions 19-22 and is not predicted to alter the protein reading-fr ame. It is unclear if this duplication will impact the protein. In summary, the clinical significance of the p.Leu19_Gln22dup variant is uncertain. -

not provided

Uncertain:1

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.15

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1220133830

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