rs35079932

chr19-40622510-G-A

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.3327G>A(p.Val1109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,613,582 control chromosomes in the GnomAD database, including 2,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2276 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.713

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-40622510-G-A is Benign according to our data. Variant chr19-40622510-G-A is described in ClinVar as [Benign]. Clinvar id is 226722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40622510-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.713 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042545.2	c.3327G>A	p.Val1109=	synonymous_variant	23/30	ENST00000396819.8
LTBP4	NM_001042544.1	c.3528G>A	p.Val1176=	synonymous_variant	26/33
LTBP4	NM_003573.2	c.3417G>A	p.Val1139=	synonymous_variant	26/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8	c.3327G>A	p.Val1109=	synonymous_variant	23/30	1	NM_001042545.2	P3

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5160 AN: 152260 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0390 AC: 9655 AN: 247548 Hom.: 240 AF XY: 0.0414 AC XY: 5571 AN XY: 134622

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0647

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0520 AC: 76015 AN: 1461204 Hom.: 2276 Cov.: 34 AF XY: 0.0521 AC XY: 37873 AN XY: 726886

Gnomad4 AFR exome AF: 0.00819

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.0619

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0445

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.0589

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0338 AC: 5156 AN: 152378 Hom.: 126 Cov.: 32 AF XY: 0.0319 AC XY: 2377 AN XY: 74512

Gnomad4 AFR AF: 0.00969

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0416

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.0555

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0510 Hom.: 332

Bravo AF: 0.0330

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0574

EpiControl AF: 0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Val1176Val in exon 26 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 5.4% (442/8252) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35079932). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

LTBP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.7
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35079932; hg19: chr19-41128415; COSMIC: COSV52584214; COSMIC: COSV52584214;