rs727505005

Positions:

• chr19-40609517-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042545.2(LTBP4):​c.1427-13C>G variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTBP4 NM_001042545.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.67

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.1427-13C>G		intron_variant		ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1628-13C>G		intron_variant			NP_001036009.1
LTBP4	NM_003573.2	c.1517-13C>G		intron_variant			NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.1427-13C>G		intron_variant		1	NM_001042545.2	ENSP00000380031.5
LTBP4	ENST00000308370.11	c.1628-13C>G		intron_variant		1		ENSP00000311905.8
LTBP4	ENST00000204005.13	c.1517-13C>G		intron_variant		1		ENSP00000204005.10
LTBP4	ENST00000598717.5	n.429-1857C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 14, 2014

The 1628-13C>G variant in LTBP4 has not been reported in individuals with pulmon ary disease and data from large population studies is insufficient to assess the frequency of this variant. This variant is located in the 3' splice region. Com putational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, additional informa tion is needed to fully assess the clinical significance of the 1628-13C>G varia nt. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.85
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727505005; hg19: chr19-41115423;