chr19-40613923-C-T

Variant names:

• chr19-40613923-C-T
• rs2077407
• NM_001042545.2:c.2565C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001042545.2(LTBP4):​c.2565C>T​(p.Asp855Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,613,452 control chromosomes in the GnomAD database, including 6,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (497 hom., cov: 31)
  • Exomes 𝑓: 0.086 (5910 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.331

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 19-40613923-C-T is Benign according to our data. Variant chr19-40613923-C-T is described in ClinVar as [Benign]. Clinvar id is 163947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40613923-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.331 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.2565C>T	p.Asp855Asp	synonymous_variant	Exon 18 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2766C>T	p.Asp922Asp	synonymous_variant	Exon 21 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.2655C>T	p.Asp885Asp	synonymous_variant	Exon 21 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2565C>T	p.Asp855Asp	synonymous_variant	Exon 18 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.0738 AC: 11206 AN: 151930 Hom.: 497 Cov.: 31

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0560

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00310

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0776

GnomAD3 exomes AF: 0.0784 AC: 19455 AN: 248080 Hom.: 907 AF XY: 0.0803 AC XY: 10830 AN XY: 134830

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.0460

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.0584

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0929

GnomAD4 exome AF: 0.0865 AC: 126351 AN: 1461404 Hom.: 5910 Cov.: 34 AF XY: 0.0867 AC XY: 63020 AN XY: 726980

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.0492

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0598

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0924

Gnomad4 OTH exome AF: 0.0858

GnomAD4 genome AF: 0.0737 AC: 11204 AN: 152048 Hom.: 497 Cov.: 31 AF XY: 0.0736 AC XY: 5472 AN XY: 74322

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.0559

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.0519

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0768

Alfa AF: 0.0833 Hom.: 461

Bravo AF: 0.0674

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp922Asp in exon 21 of LTBP4: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.0% (840/8402) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2077407). -

Oct 10, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.95
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2077407; hg19: chr19-41119829; COSMIC: COSV52587442; COSMIC: COSV52587442;