rs1220133830

Variant names:

• chr19-40601436-G-GCGCAGCTAGGGC
• rs1220133830
• NM_001042545.2:c.56_67dupTAGGGCCGCAGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2 PM4 BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.150

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]

ACMG classification

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 rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	Exon 1 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.451+1266_451+1277dupTAGGGCCGCAGC		intron_variant	Intron 4 of 32		NP_001036009.1
LTBP4	NM_003573.2	c.340+1266_340+1277dupTAGGGCCGCAGC		intron_variant	Intron 4 of 32		NP_003564.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151734 Hom.: 0 Cov.: 31

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: 9 AN: 78574 Hom.: 0 AF XY: 0.000111 AC XY: 5 AN XY: 45090

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.: 0 Cov.: 31 AF XY: 0.000252 AC XY: 162 AN XY: 643488

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: 38 AN: 151842 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74214

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.: 0

Bravo AF: 0.000128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign: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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1220133830; hg19: chr19-41107342;