dbSNP rs2290427: LTBP1:p.Pro1009Gln (chr2-33280072-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_206943.4(LTBP1):c.3026C>A(p.Pro1009Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0203 in 1,613,984 control chromosomes in the GnomAD database, including 407 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 21 hom., cov: 32)

Exomes 𝑓: 0.021 ( 386 hom. )

Consequence

LTBP1
NM_206943.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Publications

19 publications found

Variant links:

Genes affected

LTBP1 (HGNC:6714): (latent transforming growth factor beta binding protein 1) The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

LTBP1 Gene-Disease associations (from GenCC):

cutis laxa, autosomal recessive, type 2E
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

LTBP1 links:

ENSG00000285577 (HGNC:):

ENSG00000285577 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008792281).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0145 (2212/152240) while in subpopulation EAS AF = 0.0253 (131/5186). AF 95% confidence interval is 0.0217. There are 21 homozygotes in GnomAd4. There are 1018 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP1	NM_206943.4 link	c.3026C>A	p.Pro1009Gln	missense_variant	Exon 19 of 34	ENST00000404816.7	NP_996826.3	Q14766-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP1	ENST00000404816.7 link	c.3026C>A	p.Pro1009Gln	missense_variant	Exon 19 of 34	5	NM_206943.4	ENSP00000386043.2		Q14766-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2213

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0252

Gnomad SAS

AF:

0.00560

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0205

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0154

AC:

3877

AN:

251246

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.00844

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0237

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0209

AC:

30613

AN:

1461744

Hom.:

386

Cov.:

AF XY:

0.0203

AC XY:

14750

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00388

AC:

130

AN:

33476

American (AMR)

AF:

0.00865

AC:

387

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

517

AN:

26136

East Asian (EAS)

AF:

0.0400

AC:

1589

AN:

39694

South Asian (SAS)

AF:

0.00605

AC:

522

AN:

86234

European-Finnish (FIN)

AF:

0.0132

AC:

707

AN:

53416

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0230

AC:

25623

AN:

1111910

Other (OTH)

AF:

0.0183

AC:

1108

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1409

2818

4228

5637

7046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<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:

0.0145

AC:

2212

AN:

152240

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1018

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00402

AC:

167

AN:

41544

American (AMR)

AF:

0.0147

AC:

225

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.0253

AC:

131

AN:

5186

South Asian (SAS)

AF:

0.00560

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0163

AC:

173

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0205

AC:

1396

AN:

68016

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

242

363

484

605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0186

Hom.:

141

Bravo

AF:

0.0137

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0259

AC:

100

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0209

AC:

180

ExAC

AF:

0.0152

AC:

1850

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0194

EpiControl

AF:

0.0191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.;D;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;T;T;T

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;.;.;.

PhyloP100

5.4

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.7

D;D;D;D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.67

MPC

0.57

ClinPred

0.031

GERP RS

5.5

Varity_R

0.54

gMVP

0.77

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over