Genetic Variant LTBP1:p.Ala18Pro (chr2-32947376-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_206943.4(LTBP1):c.52G>C(p.Ala18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000824 in 1,213,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A18S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

LTBP1
NM_206943.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20840344).

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.52G>C	p.Ala18Pro	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.52G>C	p.Ala18Pro	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.52G>C	p.Ala18Pro	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
LTBP1	ENST00000929169.1		c.52G>C	p.Ala18Pro	missense	Exon 1 of 34	ENSP00000599228.1
LTBP1	ENST00000954823.1		c.52G>C	p.Ala18Pro	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.24e-7

AC:

AN:

1213302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

593016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24386

American (AMR)

AF:

0.00

AC:

AN:

14604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18208

East Asian (EAS)

AF:

0.00

AC:

AN:

26756

South Asian (SAS)

AF:

0.00

AC:

AN:

54904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3430

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

992500

Other (OTH)

AF:

0.00

AC:

AN:

49058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.11

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.90

PhyloP100

1.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.27

REVEL

Benign

0.19

Sift

Benign

0.045

Sift4G

Benign

0.14

Vest4

0.24

MutPred

0.45

Gain of loop (P = 0.0013)

MVP

0.25

MPC

2.1

ClinPred

0.090

GERP RS

0.85

PromoterAI

0.066

Neutral

(source)

Varity_R

0.17

gMVP

0.47

Mutation Taster

=88/12

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