rs1051303

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2257A>G(p.Thr753Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,610,370 control chromosomes in the GnomAD database, including 151,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17544 hom., cov: 32)

Exomes 𝑓: 0.42 ( 133682 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0720

Publications

53 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=3.2398105E-4).

BP6

Variant 19-40612150-A-G is Benign according to our data. Variant chr19-40612150-A-G is described in ClinVar as Benign. ClinVar VariationId is 178781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 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.2257A>G	p.Thr753Ala	missense	Exon 15 of 30	NP_001036010.1	Q8N2S1-2
LTBP4	NM_001042544.1		c.2458A>G	p.Thr820Ala	missense	Exon 18 of 33	NP_001036009.1	Q8N2S1-1
LTBP4	NM_003573.2		c.2347A>G	p.Thr783Ala	missense	Exon 18 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.2257A>G	p.Thr753Ala	missense	Exon 15 of 30	ENSP00000380031.5	Q8N2S1-2
LTBP4	ENST00000308370.11	TSL:1	c.2458A>G	p.Thr820Ala	missense	Exon 18 of 33	ENSP00000311905.8	Q8N2S1-1
LTBP4	ENST00000204005.13	TSL:1	c.2347A>G	p.Thr783Ala	missense	Exon 18 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71656

AN:

151834

Hom.:

17536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.551

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.451

GnomAD2 exomes

AF:

0.440

AC:

107030

AN:

243468

AF XY:

0.448

show subpopulations

Gnomad AFR exome

AF:

0.578

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.546

Gnomad EAS exome

AF:

0.412

Gnomad FIN exome

AF:

0.511

Gnomad NFE exome

AF:

0.414

Gnomad OTH exome

AF:

0.432

GnomAD4 exome

AF:

0.424

AC:

617917

AN:

1458418

Hom.:

133682

Cov.:

AF XY:

0.430

AC XY:

311594

AN XY:

725092

show subpopulations

African (AFR)

AF:

0.592

AC:

19790

AN:

33454

American (AMR)

AF:

0.310

AC:

13761

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14141

AN:

26048

East Asian (EAS)

AF:

0.366

AC:

14478

AN:

39584

South Asian (SAS)

AF:

0.558

AC:

47723

AN:

85578

European-Finnish (FIN)

AF:

0.511

AC:

27052

AN:

52976

Middle Eastern (MID)

AF:

0.499

AC:

2877

AN:

5760

European-Non Finnish (NFE)

AF:

0.406

AC:

450735

AN:

1110418

Other (OTH)

AF:

0.454

AC:

27360

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

19155

38310

57466

76621

95776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13934

27868

41802

55736

69670

<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:

0.472

AC:

71707

AN:

151952

Hom.:

17544

Cov.:

AF XY:

0.477

AC XY:

35408

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.579

AC:

23999

AN:

41442

American (AMR)

AF:

0.379

AC:

5785

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

1928

AN:

3470

East Asian (EAS)

AF:

0.399

AC:

2054

AN:

5150

South Asian (SAS)

AF:

0.553

AC:

2665

AN:

4822

European-Finnish (FIN)

AF:

0.528

AC:

5581

AN:

10580

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.416

AC:

28275

AN:

67900

Other (OTH)

AF:

0.451

AC:

950

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1924

3848

5773

7697

9621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.431

Hom.:

69287

Bravo

AF:

0.463

TwinsUK

AF:

0.400

AC:

1483

ALSPAC

AF:

0.400

AC:

1542

ESP6500AA

AF:

0.568

AC:

2360

ESP6500EA

AF:

0.418

AC:

3519

ExAC

AF:

0.443

AC:

53565

Asia WGS

AF:

0.484

AC:

1681

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (4)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

2.8

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.044

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.0074

MetaRNN

Benign

0.00032

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.13

PhyloP100

-0.072

PrimateAI

Benign

0.43

PROVEAN

Benign

0.99

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.028

MPC

0.33

ClinPred

0.000011

GERP RS

3.0

PromoterAI

0.055

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.33

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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