rs1220133830

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. 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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.150
• Publications: 0 publications found

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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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 VariationId is 517252.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	Exon 1 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.451+1266_451+1277dupTAGGGCCGCAGC		intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.340+1266_340+1277dupTAGGGCCGCAGC		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.56_67dupTAGGGCCGCAGC	p.Leu19_Gln22dup	disruptive_inframe_insertion	Exon 1 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.451+1266_451+1277dupTAGGGCCGCAGC		intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.340+1266_340+1277dupTAGGGCCGCAGC		intron	N/A	ENSP00000204005.10	A0A0C4DH07

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

GnomAD2 exomes AF: 0.000115 AC: 9 AN: 78574 AF XY: 0.000111

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

African (AFR) AF: 0.00 AC: 0 AN: 26558

American (AMR) AF: 0.00 AC: 0 AN: 26572

Ashkenazi Jewish (ASJ) AF: 0.0000439 AC: 1 AN: 22802

East Asian (EAS) AF: 0.00 AC: 0 AN: 28108

South Asian (SAS) AF: 0.0000563 AC: 4 AN: 71016

European-Finnish (FIN) AF: 0.000634 AC: 21 AN: 33132

Middle Eastern (MID) AF: 0.000229 AC: 1 AN: 4358

European-Non Finnish (NFE) AF: 0.000259 AC: 269 AN: 1039812

Other (OTH) AF: 0.000111 AC: 6 AN: 53868

GnomAD4 genome AF: 0.000250 AC: 38 AN: 151842 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74214

African (AFR) AF: 0.0000241 AC: 1 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000572 AC: 6 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67818

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.000128

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1220133830; hg19: chr19-41107342;