Genetic Variant LTBP4:p.Asp855Glu (chr19-40613923-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001042545.2(LTBP4):c.2565C>G(p.Asp855Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D855D) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.331

Publications

16 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: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

LTBP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LTBP4	NM_001042545.2 link	c.2565C>G	p.Asp855Glu	missense_variant	Exon 18 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1 link	c.2766C>G	p.Asp922Glu	missense_variant	Exon 21 of 33		NP_001036009.1
LTBP4	NM_003573.2 link	c.2655C>G	p.Asp885Glu	missense_variant	Exon 21 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.2565C>G	p.Asp855Glu	missense_variant	Exon 18 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111790

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

511

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.9

.;H;.;.

PhyloP100

-0.33

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.3

D;D;D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0020

D;D;D;.

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.51

MutPred

0.82

.;Gain of phosphorylation at S925 (P = 0.2307);.;.;

MVP

0.87

MPC

1.0

ClinPred

1.0

GERP RS

-1.3

PromoterAI

-0.082

Neutral

(source)

Varity_R

0.069

gMVP

0.85

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over