chr19-40611963-A-G

Position:

• chr19-40611963-A-G

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.2158A>G​(p.Thr720Ala) 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 1,610,558 control chromosomes in the GnomAD database, including 151,466 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 (17543 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133923 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6001874E-5).
• BP6: Variant 19-40611963-A-G is Benign according to our data. Variant chr19-40611963-A-G is described in ClinVar as [Benign]. Clinvar id is 163946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40611963-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	Protein	UniProt
LTBP4	NM_001042545.2	c.2158A>G	p.Thr720Ala	missense_variant	14/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2359A>G	p.Thr787Ala	missense_variant	17/33		NP_001036009.1
LTBP4	NM_003573.2	c.2248A>G	p.Thr750Ala	missense_variant	17/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2158A>G	p.Thr720Ala	missense_variant	14/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71654 AN: 151746 Hom.: 17534 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.452

GnomAD3 exomes AF: 0.439 AC: 107038 AN: 243614 Hom.: 24293 AF XY: 0.448 AC XY: 59152 AN XY: 132126

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.557

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.424 AC: 618403 AN: 1458692 Hom.: 133923 Cov.: 61 AF XY: 0.430 AC XY: 311831 AN XY: 725188

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.311

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: 151866 Hom.: 17543 Cov.: 32 AF XY: 0.477 AC XY: 35393 AN XY: 74236

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: 0.417

Gnomad4 OTH AF: 0.452

Alfa AF: 0.433 Hom.: 23801

Bravo AF: 0.463

TwinsUK AF: 0.400 AC: 1484

ALSPAC AF: 0.401 AC: 1545

ESP6500AA AF: 0.563 AC: 2374

ESP6500EA AF: 0.422 AC: 3549

ExAC AF: 0.442 AC: 53474

Asia WGS AF: 0.484 AC: 1682 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 01, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr787Ala in exon 17 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 43.7% (1840/4214) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1131620). -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.035
DANN	Benign	0.63
DEOGEN2	Benign	0.039	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.0053	T;T;T
MetaRNN	Benign	0.000016	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.46	.;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.019
MPC		0.33
ClinPred		0.0026	T
GERP RS		2.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.20

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: rs1131620; hg19: chr19-41117869; COSMIC: COSV52582827; COSMIC: COSV52582827;