rs10880

Positions:

chr19-40622404-C-T

Variant summary

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

The ENST00000396819.8(LTBP4):c.3221C>T(p.Thr1074Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,523,288 control chromosomes in the GnomAD database, including 103,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12017 hom., cov: 30)

Exomes 𝑓: 0.36 ( 91238 hom. )

Consequence

LTBP4
ENST00000396819.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.152

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.7433038E-4).

BP6

Variant 19-40622404-C-T is Benign according to our data. Variant chr19-40622404-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40622404-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 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.3221C>T	p.Thr1074Met	missense_variant	23/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1 linkuse as main transcript	c.3422C>T	p.Thr1141Met	missense_variant	26/33		NP_001036009.1
LTBP4	NM_003573.2 linkuse as main transcript	c.3311C>T	p.Thr1104Met	missense_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.3221C>T	p.Thr1074Met	missense_variant	23/30	1	NM_001042545.2	ENSP00000380031	P3	Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59448

AN:

151708

Hom.:

12007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.451

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.501

Gnomad EAS

AF:

0.337

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.484

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.375

GnomAD3 exomes

AF:

0.378

AC:

54132

AN:

143082

Hom.:

10705

AF XY:

0.386

AC XY:

29119

AN XY:

75468

show subpopulations

Gnomad AFR exome

AF:

0.461

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.500

Gnomad EAS exome

AF:

0.349

Gnomad SAS exome

AF:

0.494

Gnomad FIN exome

AF:

0.467

Gnomad NFE exome

AF:

0.347

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.361

AC:

494495

AN:

1371462

Hom.:

91238

Cov.:

AF XY:

0.366

AC XY:

245384

AN XY:

670968

show subpopulations

Gnomad4 AFR exome

AF:

0.465

Gnomad4 AMR exome

AF:

0.274

Gnomad4 ASJ exome

AF:

0.489

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.495

Gnomad4 FIN exome

AF:

0.466

Gnomad4 NFE exome

AF:

0.344

Gnomad4 OTH exome

AF:

0.386

GnomAD4 genome

AF:

0.392

AC:

59506

AN:

151826

Hom.:

12017

Cov.:

AF XY:

0.397

AC XY:

29483

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.451

Gnomad4 AMR

AF:

0.316

Gnomad4 ASJ

AF:

0.501

Gnomad4 EAS

AF:

0.337

Gnomad4 SAS

AF:

0.493

Gnomad4 FIN

AF:

0.484

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.373

Alfa

AF:

0.361

Hom.:

6580

Bravo

AF:

0.378

TwinsUK

AF:

0.345

AC:

1279

ALSPAC

AF:

0.341

AC:

1316

ESP6500AA

AF:

0.424

AC:

1675

ESP6500EA

AF:

0.345

AC:

2814

ExAC

AF:

0.308

AC:

34733

Asia WGS

AF:

0.419

AC:

1455

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr1141Met in exon 26 of LTBP4: This variant is not expected to have clinical si gnificance because it has been identified in 42.4% (1675/3950) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs10880). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.090

T;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.00027

T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Uncertain

0.63

REVEL

Benign

0.17

Sift4G

Benign

0.10

T;T;T

Polyphen

0.052

.;B;.

Vest4

0.056

MPC

0.36

ClinPred

0.014

GERP RS

3.8

Varity_R

0.038

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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