19-40606426-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001042545.2(LTBP4):c.891C>T(p.Gly297=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,594,500 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G297G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 25 hom. )

Consequence

LTBP4
NM_001042545.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.80

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 19-40606426-C-T is Benign according to our data. Variant chr19-40606426-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40606426-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.8 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0036 (548/152322) while in subpopulation NFE AF= 0.0052 (354/68022). AF 95% confidence interval is 0.00476. There are 2 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LTBP4	NM_001042545.2 linkuse as main transcript	c.891C>T	p.Gly297=	synonymous_variant	6/30	ENST00000396819.8
LTBP4	NM_001042544.1 linkuse as main transcript	c.1092C>T	p.Gly364=	synonymous_variant	9/33
LTBP4	NM_003573.2 linkuse as main transcript	c.981C>T	p.Gly327=	synonymous_variant	9/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8 linkuse as main transcript	c.891C>T	p.Gly297=	synonymous_variant	6/30	1	NM_001042545.2	P3	Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

549

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00520

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00394

AC:

864

AN:

219296

Hom.:

AF XY:

0.00420

AC XY:

505

AN XY:

120298

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00224

Gnomad EAS exome

AF:

0.0000617

Gnomad SAS exome

AF:

0.00388

Gnomad FIN exome

AF:

0.00825

Gnomad NFE exome

AF:

0.00519

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00396

AC:

5717

AN:

1442178

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2852

AN XY:

714816

show subpopulations

Gnomad4 AFR exome

AF:

0.000514

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00194

Gnomad4 EAS exome

AF:

0.0000516

Gnomad4 SAS exome

AF:

0.00365

Gnomad4 FIN exome

AF:

0.00720

Gnomad4 NFE exome

AF:

0.00426

Gnomad4 OTH exome

AF:

0.00322

GnomAD4 genome

AF:

0.00360

AC:

548

AN:

152322

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

282

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.00520

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00456

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LTBP4: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Gly364Gly in exon 9 of LTBP4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.4% (30/8342) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS). -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LTBP4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

Cadd

Benign

1.8

Dann

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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