19-40601522-C-G

Variant names:

• chr19-40601522-C-G
• NM_001042545.2:c.135C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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	c.135C>G	p.Cys45Trp	missense_variant	Exon 1 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.451+1345C>G		intron_variant	Intron 4 of 32		NP_001036009.1
LTBP4	NM_003573.2	c.340+1345C>G		intron_variant	Intron 4 of 32		NP_003564.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1341554 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 661844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.43e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.18	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.72
MutPred		0.79		Gain of MoRF binding (P = 0.0139);
MVP		0.69
ClinPred		0.39	T
GERP RS		1.6

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41107428;