Genetic Variant LTBP1:p.Val138Ile (chr2-32947736-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_206943.4(LTBP1):c.412G>A(p.Val138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,386,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V138L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

LTBP1
NM_206943.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.774

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

LTBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061026603).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206943.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	NM_206943.4	MANE Select	c.412G>A	p.Val138Ile	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.412G>A	p.Val138Ile	missense	Exon 1 of 34	NP_001381834.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP1	ENST00000404816.7	TSL:5 MANE Select	c.412G>A	p.Val138Ile	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
LTBP1	ENST00000929169.1		c.412G>A	p.Val138Ile	missense	Exon 1 of 34	ENSP00000599228.1
LTBP1	ENST00000954823.1		c.412G>A	p.Val138Ile	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000578

AC:

AN:

173140

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1386458

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

688906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28642

American (AMR)

AF:

0.00

AC:

AN:

35360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24068

East Asian (EAS)

AF:

0.00

AC:

AN:

31760

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1076240

Other (OTH)

AF:

0.00

AC:

AN:

56710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.00000879

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

0.77

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.020

REVEL

Benign

0.14

Sift

Benign

0.14

Sift4G

Benign

0.41

Vest4

0.047

MutPred

0.14

Loss of ubiquitination at K142 (P = 0.1473)

MVP

0.043

MPC

0.11

ClinPred

0.072

GERP RS

3.1

Varity_R

0.066

gMVP

0.042

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over