19-40611963-A-G

Variant names:

• chr19-40611963-A-G
• rs1131620
• NM_001042545.2:c.2158A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T720T) has been classified as Likely 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
• Publications: 58 publications found

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 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 163946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.2158A>G	p.Thr720Ala	missense_variant	Exon 14 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2359A>G	p.Thr787Ala	missense_variant	Exon 17 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.2248A>G	p.Thr750Ala	missense_variant	Exon 17 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2158A>G	p.Thr720Ala	missense_variant	Exon 14 of 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

GnomAD2 exomes AF: 0.439 AC: 107038 AN: 243614 AF XY: 0.448

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 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

African (AFR) AF: 0.592 AC: 19784 AN: 33436

American (AMR) AF: 0.311 AC: 13780 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 14125 AN: 26018

East Asian (EAS) AF: 0.366 AC: 14491 AN: 39606

South Asian (SAS) AF: 0.558 AC: 47790 AN: 85662

European-Finnish (FIN) AF: 0.511 AC: 27184 AN: 53198

Middle Eastern (MID) AF: 0.499 AC: 2873 AN: 5760

European-Non Finnish (NFE) AF: 0.406 AC: 450998 AN: 1110396

Other (OTH) AF: 0.454 AC: 27378 AN: 60272

GnomAD4 genome AF: 0.472 AC: 71707 AN: 151866 Hom.: 17543 Cov.: 32 AF XY: 0.477 AC XY: 35393 AN XY: 74236

African (AFR) AF: 0.579 AC: 23980 AN: 41414

American (AMR) AF: 0.379 AC: 5790 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1926 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2057 AN: 5150

South Asian (SAS) AF: 0.553 AC: 2657 AN: 4804

European-Finnish (FIN) AF: 0.528 AC: 5582 AN: 10566

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28295 AN: 67898

Other (OTH) AF: 0.452 AC: 950 AN: 2102

Alfa AF: 0.431 Hom.: 48892

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 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.

Dec 01, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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).

Sep 29, 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

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

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	0.0	.;N;.
PhyloP100		-2.0
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
Vest4		0.019
ClinPred		0.0026	T
GERP RS		2.5
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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