rs34545902

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042545.2(LTBP4):c.1300T>A(p.Ser434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00976 in 1,612,550 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 376 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 387 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.25

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013553202).

BP6

Variant 19-40608363-T-A is Benign according to our data. Variant chr19-40608363-T-A is described in ClinVar as [Benign]. Clinvar id is 178780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40608363-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LTBP4	NM_001042545.2 linkuse as main transcript	c.1300T>A	p.Ser434Thr	missense_variant	8/30	ENST00000396819.8
LTBP4	NM_001042544.1 linkuse as main transcript	c.1501T>A	p.Ser501Thr	missense_variant	11/33
LTBP4	NM_003573.2 linkuse as main transcript	c.1390T>A	p.Ser464Thr	missense_variant	11/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8 linkuse as main transcript	c.1300T>A	p.Ser434Thr	missense_variant	8/30	1	NM_001042545.2	P3	Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6302

AN:

152202

Hom.:

374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00931

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0123

AC:

3013

AN:

245808

Hom.:

153

AF XY:

0.00989

AC XY:

1320

AN XY:

133496

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.00835

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.00806

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00888

GnomAD4 exome

AF:

0.00646

AC:

9431

AN:

1460230

Hom.:

387

Cov.:

AF XY:

0.00587

AC XY:

4264

AN XY:

726190

show subpopulations

Gnomad4 AFR exome

AF:

0.141

Gnomad4 AMR exome

AF:

0.00916

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000419

Gnomad4 FIN exome

AF:

0.00778

Gnomad4 NFE exome

AF:

0.00227

Gnomad4 OTH exome

AF:

0.0119

GnomAD4 genome

AF:

0.0414

AC:

6311

AN:

152320

Hom.:

376

Cov.:

AF XY:

0.0408

AC XY:

3041

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.0200

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00931

Gnomad4 NFE

AF:

0.00270

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.00925

Hom.:

Bravo

AF:

0.0474

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.127

AC:

509

ESP6500EA

AF:

0.00241

AC:

ExAC

AF:

0.0138

AC:

1663

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00405

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Ser501Thr in exon 11 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 12.7% (509/4004) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34545902). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.044

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.70

T;T;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.43

N;N;N

REVEL

Benign

0.087

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.016

.;B;.

Vest4

0.12

MPC

0.31

ClinPred

0.000020

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.033

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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