rs34093919

Positions:

• chr19-40611394-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042545.2(LTBP4):​c.2053G>A​(p.Asp685Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0101 in 1,603,676 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.010 (119 hom.)
• Consequence: LTBP4 NM_001042545.2 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.62

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 -16 ACMG points.

• BP6: Variant 19-40611394-G-A is Benign according to our data. Variant chr19-40611394-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 386527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40611394-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00732 (1115/152356) while in subpopulation NFE AF= 0.0109 (744/68034). AF 95% confidence interval is 0.0103. There are 11 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.2053G>A	p.Asp685Asn	missense_variant, splice_region_variant	13/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2254G>A	p.Asp752Asn	missense_variant, splice_region_variant	16/33		NP_001036009.1
LTBP4	NM_003573.2	c.2143G>A	p.Asp715Asn	missense_variant, splice_region_variant	16/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2053G>A	p.Asp685Asn	missense_variant, splice_region_variant	13/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1115 AN: 152238 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00769 AC: 1838 AN: 239032 Hom.: 11 AF XY: 0.00781 AC XY: 1023 AN XY: 130936

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000409

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.0103 AC: 15013 AN: 1451320 Hom.: 119 Cov.: 32 AF XY: 0.0101 AC XY: 7322 AN XY: 721674

Gnomad4 AFR exome AF: 0.000932

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.00660

GnomAD4 genome AF: 0.00732 AC: 1115 AN: 152356 Hom.: 11 Cov.: 32 AF XY: 0.00801 AC XY: 597 AN XY: 74512

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00993 Hom.: 15

Bravo AF: 0.00560

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00264 AC: 10

ESP6500EA AF: 0.00782 AC: 64

ExAC AF: 0.00813 AC: 980

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.00824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2018	This variant is associated with the following publications: (PMID: 30804560) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LTBP4: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	p.Asp752Asn in exon 16 of LTBP4: This variant is not expected to have clinical s ignificance because it has been identified in 2.3% (150/6532) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs34093919). -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0092	T;T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.054	T;D;T
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.50	.;P;.
Vest4		0.56
MVP		0.76
MPC		0.95
ClinPred		0.035	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34093919; hg19: chr19-41117300;