dbSNP rs33937741: LTBP4:p.Arg568Ser (chr19-40610549-C-A) – 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_001042545.2(LTBP4):c.1702C>A(p.Arg568Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. R568G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.126

Publications

9 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26258993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.1702C>A	p.Arg568Ser	missense_variant	Exon 12 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.1903C>A	p.Arg635Ser	missense_variant	Exon 15 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.1792C>A	p.Arg598Ser	missense_variant	Exon 15 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.1702C>A	p.Arg568Ser	missense_variant	Exon 12 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716524

African (AFR)

AF:

0.00

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

43178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39402

South Asian (SAS)

AF:

0.00

AC:

AN:

84800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107660

Other (OTH)

AF:

0.00

AC:

AN:

59904

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.15

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

-0.88

.;N;.

PhyloP100

0.13

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.88

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.49

.;P;.

Vest4

0.55

MutPred

0.35

.;Gain of glycosylation at R635 (P = 0.0522);.;

MVP

0.43

MPC

0.80

ClinPred

0.74

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.20

gMVP

0.56

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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