dbSNP rs185400394: LTBP4:p.Cys45Trp (chr19-40601522-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001042545.2(LTBP4):c.135C>G(p.Cys45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,341,554 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. C45C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.653

Publications

0 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.135C>G	p.Cys45Trp	missense_variant	Exon 1 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.451+1345C>G		intron_variant	Intron 4 of 32		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.340+1345C>G		intron_variant	Intron 4 of 32		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.135C>G	p.Cys45Trp	missense_variant	Exon 1 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.45e-7

AC:

AN:

1341554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

661844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27202

American (AMR)

AF:

0.00

AC:

AN:

30666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23762

East Asian (EAS)

AF:

0.00

AC:

AN:

30468

South Asian (SAS)

AF:

0.00

AC:

AN:

74682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4574

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060650

Other (OTH)

AF:

0.00

AC:

AN:

55868

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.18

PhyloP100

0.65

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.72

MutPred

0.79

Gain of MoRF binding (P = 0.0139);

MVP

0.69

ClinPred

0.39

GERP RS

1.6

PromoterAI

-0.050

Neutral

(source)

Mutation Taster

=71/29

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over