rs185400394

Positions:

• chr19-40601522-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001042545.2(LTBP4):​c.135C>T​(p.Cys45Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,493,690 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (52 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.653

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-40601522-C-T is Benign according to our data. Variant chr19-40601522-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40601522-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.653 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00626 (952/152138) while in subpopulation NFE AF= 0.00954 (648/67952). AF 95% confidence interval is 0.00893. There are 6 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.135C>T	p.Cys45Cys	synonymous_variant	1/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.451+1345C>T		intron_variant			NP_001036009.1
LTBP4	NM_003573.2	c.340+1345C>T		intron_variant			NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.135C>T	p.Cys45Cys	synonymous_variant	1/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 954 AN: 152030 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00547 AC: 525 AN: 95970 Hom.: 5 AF XY: 0.00527 AC XY: 284 AN XY: 53914

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00130

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.00915

Gnomad OTH exome AF: 0.00630

GnomAD4 exome AF: 0.00685 AC: 9183 AN: 1341552 Hom.: 52 Cov.: 31 AF XY: 0.00691 AC XY: 4571 AN XY: 661842

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.0000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.00763

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00626 AC: 952 AN: 152138 Hom.: 6 Cov.: 31 AF XY: 0.00640 AC XY: 476 AN XY: 74388

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.00954

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00865 Hom.: 5

Bravo AF: 0.00487

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LTBP4: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 06, 2015

p.Cys45Cys in exon 1A 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 0.7% (20/2846) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs185400394). -

LTBP4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs185400394; hg19: chr19-41107428;