rs55815263

Variant names:

• chr19-40599071-C-T
• rs55815263
• ENST00000308370.11:c.147-126C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042544.1(LTBP4):​c.147-126C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 853,032 control chromosomes in the GnomAD database, including 16,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2637 hom., cov: 31)
  • Exomes 𝑓: 0.20 (14112 hom.)
• Consequence: LTBP4 NM_001042544.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.499
• Publications: 8 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-40599071-C-T is Benign according to our data. Variant chr19-40599071-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042544.1. 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_001042544.1		c.147-126C>T		intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.17-126C>T		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000308370.11	TSL:1	c.147-126C>T		intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.17-126C>T		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000594537.2	TSL:5	n.95-126C>T		intron	N/A	ENSP00000480629.1	A0A087WWZ7

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27477 AN: 151948 Hom.: 2642 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.195 AC: 136770 AN: 700964 Hom.: 14112 AF XY: 0.201 AC XY: 74315 AN XY: 369292

African (AFR) AF: 0.156 AC: 2828 AN: 18178

American (AMR) AF: 0.132 AC: 4574 AN: 34740

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 4307 AN: 20752

East Asian (EAS) AF: 0.261 AC: 8503 AN: 32528

South Asian (SAS) AF: 0.287 AC: 18593 AN: 64814

European-Finnish (FIN) AF: 0.233 AC: 11249 AN: 48310

Middle Eastern (MID) AF: 0.200 AC: 866 AN: 4330

European-Non Finnish (NFE) AF: 0.178 AC: 78888 AN: 442246

Other (OTH) AF: 0.199 AC: 6962 AN: 35066

GnomAD4 genome AF: 0.181 AC: 27468 AN: 152068 Hom.: 2637 Cov.: 31 AF XY: 0.185 AC XY: 13752 AN XY: 74342

African (AFR) AF: 0.158 AC: 6550 AN: 41452

American (AMR) AF: 0.147 AC: 2253 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1442 AN: 5172

South Asian (SAS) AF: 0.274 AC: 1320 AN: 4814

European-Finnish (FIN) AF: 0.250 AC: 2648 AN: 10578

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11975 AN: 67984

Other (OTH) AF: 0.175 AC: 369 AN: 2104

Alfa AF: 0.181 Hom.: 597

Bravo AF: 0.172

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs55815263; hg19: chr19-41104977; COSMIC: COSV52593103; COSMIC: COSV52593103;