19-40601522-C-G

Variant names:

• chr19-40601522-C-G
• rs185400394
• NM_001042545.2:c.135C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000396819.8(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 ENST00000396819.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• Publications: 0 publications found

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396819.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.135C>G	p.Cys45Trp	missense	Exon 1 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.451+1345C>G		intron	N/A	NP_001036009.1
	LTBP4	NM_003573.2		c.340+1345C>G		intron	N/A	NP_003564.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.135C>G	p.Cys45Trp	missense	Exon 1 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.451+1345C>G		intron	N/A	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.340+1345C>G		intron	N/A	ENSP00000204005.10

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

African (AFR) AF: 0.00 AC: 0 AN: 27202

American (AMR) AF: 0.00 AC: 0 AN: 30666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23762

East Asian (EAS) AF: 0.00 AC: 0 AN: 30468

South Asian (SAS) AF: 0.00 AC: 0 AN: 74682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4574

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060650

Other (OTH) AF: 0.00 AC: 0 AN: 55868

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
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
PhyloP100		0.65
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
PromoterAI		-0.050	Neutral
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs185400394; hg19: chr19-41107428;