rs7367

Positions:

• chr19-40623937-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001042545.2(LTBP4):​c.3687C>T​(p.Asp1229Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,613,160 control chromosomes in the GnomAD database, including 144,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20872 hom., cov: 32)
  • Exomes 𝑓: 0.40 (123676 hom.)
• Consequence: LTBP4 NM_001042545.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.517

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-40623937-C-T is Benign according to our data. Variant chr19-40623937-C-T is described in ClinVar as [Benign]. Clinvar id is 163950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40623937-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.517 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.3687C>T	p.Asp1229Asp	splice_region_variant, synonymous_variant	26/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.3888C>T	p.Asp1296Asp	splice_region_variant, synonymous_variant	29/33		NP_001036009.1
LTBP4	NM_003573.2	c.3777C>T	p.Asp1259Asp	splice_region_variant, synonymous_variant	29/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.3687C>T	p.Asp1229Asp	splice_region_variant, synonymous_variant	26/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75512 AN: 152018 Hom.: 20830 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.430 AC: 106381 AN: 247670 Hom.: 24242 AF XY: 0.433 AC XY: 58270 AN XY: 134562

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.404 AC: 590242 AN: 1461024 Hom.: 123676 Cov.: 49 AF XY: 0.408 AC XY: 296745 AN XY: 726732

Gnomad4 AFR exome AF: 0.763

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.521

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.439

GnomAD4 genome AF: 0.497 AC: 75612 AN: 152136 Hom.: 20872 Cov.: 32 AF XY: 0.499 AC XY: 37159 AN XY: 74394

Gnomad4 AFR AF: 0.742

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.503

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.456

Alfa AF: 0.438 Hom.: 12196

Bravo AF: 0.494

Asia WGS AF: 0.458 AC: 1590 AN: 3478

EpiCase AF: 0.399

EpiControl AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asp1296Asp in exon 29 of LTBP4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 40.0% (3347/8358) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7367). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs7367; hg19: chr19-41129842;