19-40610549-C-G

Variant names:

• chr19-40610549-C-G
• rs33937741
• NM_001042545.2:c.1702C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042545.2(LTBP4):​c.1702C>G​(p.Arg568Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 1,593,254 control chromosomes in the GnomAD database, including 1,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1576 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.126

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003421694).
• BP6: Variant 19-40610549-C-G is Benign according to our data. Variant chr19-40610549-C-G is described in ClinVar as [Benign]. Clinvar id is 329310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40610549-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0288 (4385/152318) while in subpopulation NFE AF= 0.0456 (3105/68032). AF 95% confidence interval is 0.0443. There are 82 homozygotes in gnomad4. There are 2005 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 82 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.1702C>G	p.Arg568Gly	missense_variant	Exon 12 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1903C>G	p.Arg635Gly	missense_variant	Exon 15 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.1792C>G	p.Arg598Gly	missense_variant	Exon 15 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.1702C>G	p.Arg568Gly	missense_variant	Exon 12 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4387 AN: 152200 Hom.: 82 Cov.: 33

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0275 AC: 5921 AN: 215696 Hom.: 130 AF XY: 0.0277 AC XY: 3299 AN XY: 119106

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0000593

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0431 AC: 62133 AN: 1440936 Hom.: 1576 Cov.: 32 AF XY: 0.0421 AC XY: 30184 AN XY: 716438

Gnomad4 AFR exome AF: 0.00719

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0436

Gnomad4 NFE exome AF: 0.0503

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0288 AC: 4385 AN: 152318 Hom.: 82 Cov.: 33 AF XY: 0.0269 AC XY: 2005 AN XY: 74480

Gnomad4 AFR AF: 0.00861

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0311 Hom.: 37

Bravo AF: 0.0273

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.00630 AC: 26

ESP6500EA AF: 0.0420 AC: 351

ExAC AF: 0.0254 AC: 3060

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 30, 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. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg635Gly in exon 15 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 4.2% (351/8364) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs33937741). -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Apr 02, 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.17	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.43	.;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.011	D;D;D
Sift4G	Benign	0.28	T;T;T
Polyphen		0.83	.;P;.
Vest4		0.47
MPC		1.0
ClinPred		0.042	T
GERP RS		2.8
Varity_R		0.27
gMVP		0.60

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: rs33937741; hg19: chr19-41116455;