19-40611963-A-C

Variant names:

• chr19-40611963-A-C
• rs1131620
• NM_001042545.2:c.2158A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042545.2(LTBP4):​c.2158A>C​(p.Thr720Pro) 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. 17/21 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. T720A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01
• Publications: 58 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033124477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. 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.2158A>C	p.Thr720Pro	missense	Exon 14 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.2359A>C	p.Thr787Pro	missense	Exon 17 of 33	NP_001036009.1
	LTBP4	NM_003573.2		c.2248A>C	p.Thr750Pro	missense	Exon 17 of 33	NP_003564.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.2158A>C	p.Thr720Pro	missense	Exon 14 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.2359A>C	p.Thr787Pro	missense	Exon 17 of 33	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.2248A>C	p.Thr750Pro	missense	Exon 17 of 33	ENSP00000204005.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 48892

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.49
DANN	Benign	0.79
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.0087	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.32		Loss of glycosylation at T787 (P = 0.0573)
MVP		0.15
MPC		0.44
ClinPred		0.39	T
GERP RS		2.5
PromoterAI		0.0012	Neutral
Varity_R		0.11
gMVP		0.49
Mutation Taster		=99/1	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: rs1131620; hg19: chr19-41117869;