dbSNP rs746506861: LTBP4:p.Pro71Ala (chr19-40601598-C-G) – 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.211C>G(p.Pro71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000797 in 1,255,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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. P71S) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.336

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25116092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.211C>G	p.Pro71Ala	missense_variant	Exon 1 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.451+1421C>G		intron_variant	Intron 4 of 32		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.340+1421C>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.211C>G	p.Pro71Ala	missense_variant	Exon 1 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.97e-7

AC:

AN:

1255178

Hom.:

Cov.:

AF XY:

0.00000163

AC XY:

AN XY:

614170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24842

American (AMR)

AF:

0.00

AC:

AN:

15346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18856

East Asian (EAS)

AF:

0.00

AC:

AN:

28324

South Asian (SAS)

AF:

0.0000167

AC:

AN:

59950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1020874

Other (OTH)

AF:

0.00

AC:

AN:

51780

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

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.036

Eigen_PC

Benign

0.00073

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.65

PhyloP100

0.34

PROVEAN

Benign

-0.010

REVEL

Benign

0.18

Sift

Benign

0.46

Sift4G

Benign

0.73

Vest4

0.27

MutPred

0.31

Gain of catalytic residue at P71 (P = 0.0301);

MVP

0.53

ClinPred

0.41

GERP RS

2.7

PromoterAI

0.050

Neutral

(source)

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over