rs41470347

Positions:

• chr19-40611848-C-A
• chr19-40611848-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):​c.2054-11C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,604,842 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (367 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5316 hom.)
• Consequence: LTBP4 NM_001042545.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.306

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-40611848-C-A is Benign according to our data. Variant chr19-40611848-C-A is described in ClinVar as [Benign]. Clinvar id is 226719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40611848-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042545.2	c.2054-11C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396819.8
LTBP4	NM_001042544.1	c.2255-11C>A		splice_polypyrimidine_tract_variant, intron_variant
LTBP4	NM_003573.2	c.2144-11C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8	c.2054-11C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042545.2	P3

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8392 AN: 152024 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0596 AC: 14004 AN: 234946 Hom.: 537 AF XY: 0.0624 AC XY: 7924 AN XY: 127076

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0396

Gnomad ASJ exome AF: 0.0963

Gnomad EAS exome AF: 0.000231

Gnomad SAS exome AF: 0.0456

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0874

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.0808 AC: 117335 AN: 1452702 Hom.: 5316 Cov.: 32 AF XY: 0.0803 AC XY: 57908 AN XY: 721446

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0414

Gnomad4 ASJ exome AF: 0.0969

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.0295

Gnomad4 NFE exome AF: 0.0921

Gnomad4 OTH exome AF: 0.0767

GnomAD4 genome AF: 0.0551 AC: 8385 AN: 152140 Hom.: 367 Cov.: 32 AF XY: 0.0513 AC XY: 3813 AN XY: 74366

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0532

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.000778

Gnomad4 SAS AF: 0.0407

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0872

Gnomad4 OTH AF: 0.0635

Alfa AF: 0.0799 Hom.: 145

Bravo AF: 0.0565

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	2255-11C>A in intron 16 of LTBP4: This variant is not expected to have clinical significance because it has been identified in 8.2% (683/8378) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs41470347). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	- -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs41470347; hg19: chr19-41117754;