19-40622404-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042545.2(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. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1074R) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.36 ( 91238 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.152

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LTBP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 178782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP4	NM_001042545.2	MANE Select	c.3221C>T	p.Thr1074Met	missense	Exon 23 of 30	NP_001036010.1	Q8N2S1-2
LTBP4	NM_001042544.1		c.3422C>T	p.Thr1141Met	missense	Exon 26 of 33	NP_001036009.1	Q8N2S1-1
LTBP4	NM_003573.2		c.3311C>T	p.Thr1104Met	missense	Exon 26 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.3221C>T	p.Thr1074Met	missense	Exon 23 of 30	ENSP00000380031.5	Q8N2S1-2
LTBP4	ENST00000308370.11	TSL:1	c.3422C>T	p.Thr1141Met	missense	Exon 26 of 33	ENSP00000311905.8	Q8N2S1-1
LTBP4	ENST00000204005.13	TSL:1	c.3311C>T	p.Thr1104Met	missense	Exon 26 of 33	ENSP00000204005.10	A0A0C4DH07

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

GnomAD2 exomes

AF:

0.378

AC:

54132

AN:

143082

AF XY:

0.386

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 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

African (AFR)

AF:

0.465

AC:

14729

AN:

31706

American (AMR)

AF:

0.274

AC:

9671

AN:

35300

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

11104

AN:

22702

East Asian (EAS)

AF:

0.303

AC:

11003

AN:

36312

South Asian (SAS)

AF:

0.495

AC:

36751

AN:

74310

European-Finnish (FIN)

AF:

0.466

AC:

22523

AN:

48360

Middle Eastern (MID)

AF:

0.430

AC:

2353

AN:

5474

European-Non Finnish (NFE)

AF:

0.344

AC:

364453

AN:

1060594

Other (OTH)

AF:

0.386

AC:

21908

AN:

56704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

16339

32678

49018

65357

81696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12168

24336

36504

48672

60840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.392

AC:

59506

AN:

151826

Hom.:

12017

Cov.:

AF XY:

0.397

AC XY:

29483

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.451

AC:

18676

AN:

41374

American (AMR)

AF:

0.316

AC:

4824

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

1737

AN:

3470

East Asian (EAS)

AF:

0.337

AC:

1735

AN:

5148

South Asian (SAS)

AF:

0.493

AC:

2374

AN:

4812

European-Finnish (FIN)

AF:

0.484

AC:

5111

AN:

10558

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.352

AC:

23895

AN:

67880

Other (OTH)

AF:

0.373

AC:

785

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1795

3590

5386

7181

8976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.366

Hom.:

11030

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (3)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.090

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.61

MetaRNN

Benign

0.00027

MetaSVM

Benign

-0.98

PhyloP100

0.15

PrimateAI

Uncertain

0.63

REVEL

Benign

0.17

Sift4G

Benign

0.10

Polyphen

0.052

Vest4

0.056

MPC

0.36

ClinPred

0.014

GERP RS

3.8

Varity_R

0.038

gMVP

0.32

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over