rs1051303

chr19-40612150-A-Gchr19-40612150-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):c.2257A>G(p.Thr753Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,610,370 control chromosomes in the GnomAD database, including 151,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17544 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133682 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0720

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=3.2398105E-4).
• BP6: Variant 19-40612150-A-G is Benign according to our data. Variant chr19-40612150-A-G is described in ClinVar as [Benign]. Clinvar id is 178781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40612150-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042545.2	c.2257A>G	p.Thr753Ala	missense_variant	15/30	ENST00000396819.8
LTBP4	NM_001042544.1	c.2458A>G	p.Thr820Ala	missense_variant	18/33
LTBP4	NM_003573.2	c.2347A>G	p.Thr783Ala	missense_variant	18/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8	c.2257A>G	p.Thr753Ala	missense_variant	15/30	1	NM_001042545.2	P3

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71656 AN: 151834 Hom.: 17536 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.451

GnomAD3 exomes AF: 0.440 AC: 107030 AN: 243468 Hom.: 24222 AF XY: 0.448 AC XY: 59099 AN XY: 131998

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.412

Gnomad SAS exome AF: 0.556

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.424 AC: 617917 AN: 1458418 Hom.: 133682 Cov.: 52 AF XY: 0.430 AC XY: 311594 AN XY: 725092

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.558

Gnomad4 FIN exome AF: 0.511

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.472 AC: 71707 AN: 151952 Hom.: 17544 Cov.: 32 AF XY: 0.477 AC XY: 35408 AN XY: 74296

Gnomad4 AFR AF: 0.579

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.451

Alfa AF: 0.426 Hom.: 34283

Bravo AF: 0.463

TwinsUK AF: 0.400 AC: 1483

ALSPAC AF: 0.400 AC: 1542

ESP6500AA AF: 0.568 AC: 2360

ESP6500EA AF: 0.418 AC: 3519

ExAC AF: 0.443 AC: 53565

Asia WGS AF: 0.484 AC: 1681 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 01, 2014	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr820Ala in exon 18 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 43.2% (1798/4158) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1051303). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.8
Dann	Benign	0.52
DEOGEN2	Benign	0.044	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.0074	T;T;T
MetaRNN	Benign	0.00032	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.99	N;N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.028
MPC		0.33
ClinPred		0.000011	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1051303; hg19: chr19-41118056; COSMIC: COSV52582851; COSMIC: COSV52582851;