rs1220133830

Positions:

chr19-40601436-G-GCGCAGCTAGGGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PM4BP6BS1

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. 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

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 links:

LTBP4 (HGNC:):

LTBP4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 submissions are: {Likely_benign=1, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2 linkuse as main transcript	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	1/30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 linkuse as main transcript	c.451+1266_451+1277dupTAGGGCCGCAGC		intron_variant			NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 linkuse as main transcript	c.340+1266_340+1277dupTAGGGCCGCAGC		intron_variant			NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 linkuse as main transcript	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	1/30	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

GnomAD3 exomes

AF:

0.000115

AC:

AN:

78574

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

45090

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 SAS exome

AF:

0.0000606

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000439

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000563

Gnomad4 FIN exome

AF:

0.000634

Gnomad4 NFE exome

AF:

0.000259

Gnomad4 OTH exome

AF:

0.000111

GnomAD4 genome

AF:

0.000250

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000572

Gnomad4 NFE

AF:

0.000442

Gnomad4 OTH

AF:

0.00

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

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2017	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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over