19-40606426-C-T

Variant names:

• chr19-40606426-C-T
• rs374427407
• NM_001042545.2:c.891C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001042545.2(LTBP4):​c.891C>T​(p.Gly297Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,594,500 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (25 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.80

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=-0.58).
• BP6: Variant 19-40606426-C-T is Benign according to our data. Variant chr19-40606426-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40606426-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0036 (548/152322) while in subpopulation NFE AF= 0.0052 (354/68022). AF 95% confidence interval is 0.00476. There are 2 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.891C>T	p.Gly297Gly	synonymous_variant	Exon 6 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1092C>T	p.Gly364Gly	synonymous_variant	Exon 9 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.981C>T	p.Gly327Gly	synonymous_variant	Exon 9 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.891C>T	p.Gly297Gly	synonymous_variant	Exon 6 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00394 AC: 864 AN: 219296 Hom.: 2 AF XY: 0.00420 AC XY: 505 AN XY: 120298

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.0000617

Gnomad SAS exome AF: 0.00388

Gnomad FIN exome AF: 0.00825

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00396 AC: 5717 AN: 1442178 Hom.: 25 Cov.: 40 AF XY: 0.00399 AC XY: 2852 AN XY: 714816

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00194

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.00720

Gnomad4 NFE exome AF: 0.00426

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.00360 AC: 548 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74476

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00810

Gnomad4 NFE AF: 0.00520

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00456 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LTBP4: BP4, BP7, BS2 -

Jun 15, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly364Gly in exon 9 of LTBP4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.4% (30/8342) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS). -

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. -

LTBP4-related disorder Benign:1

Sep 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.58
CADD	Benign	1.8
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs374427407; hg19: chr19-41112332; COSMIC: COSV99180287; COSMIC: COSV99180287;