19-40622510-G-A

Position:

chr19-40622510-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001042545.2(LTBP4):c.3327G>A(p.Val1109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,613,582 control chromosomes in the GnomAD database, including 2,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 126 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2276 hom. )

Consequence

LTBP4
NM_001042545.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.713

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-40622510-G-A is Benign according to our data. Variant chr19-40622510-G-A is described in ClinVar as [Benign]. Clinvar id is 226722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40622510-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.713 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LTBP4	NM_001042545.2 linkuse as main transcript	c.3327G>A	p.Val1109=	synonymous_variant	23/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1 linkuse as main transcript	c.3528G>A	p.Val1176=	synonymous_variant	26/33		NP_001036009.1
LTBP4	NM_003573.2 linkuse as main transcript	c.3417G>A	p.Val1139=	synonymous_variant	26/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 linkuse as main transcript	c.3327G>A	p.Val1109=	synonymous_variant	23/30	1	NM_001042545.2	ENSP00000380031	P3	Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5160

AN:

152260

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0555

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0390

AC:

9655

AN:

247548

Hom.:

240

AF XY:

0.0414

AC XY:

5571

AN XY:

134622

show subpopulations

Gnomad AFR exome

AF:

0.00866

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0647

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0448

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0562

Gnomad OTH exome

AF:

0.0438

GnomAD4 exome

AF:

0.0520

AC:

76015

AN:

1461204

Hom.:

2276

Cov.:

AF XY:

0.0521

AC XY:

37873

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00819

Gnomad4 AMR exome

AF:

0.0186

Gnomad4 ASJ exome

AF:

0.0619

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0445

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.0589

Gnomad4 OTH exome

AF:

0.0458

GnomAD4 genome

AF:

0.0338

AC:

5156

AN:

152378

Hom.:

126

Cov.:

AF XY:

0.0319

AC XY:

2377

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00969

Gnomad4 AMR

AF:

0.0210

Gnomad4 ASJ

AF:

0.0579

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0416

Gnomad4 FIN

AF:

0.0158

Gnomad4 NFE

AF:

0.0555

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.0510

Hom.:

332

Bravo

AF:

0.0330

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0574

EpiControl

AF:

0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val1176Val in exon 26 of LTBP4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 5.4% (442/8252) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35079932). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LTBP4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 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

-0.76

CADD

Benign

3.7

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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