rs114749335

chr19-40608301-G-Achr19-40608301-G-T

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.1238G>A(p.Gly413Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,613,792 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.528

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=0.008038253).
• BP6: Variant 19-40608301-G-A is Benign according to our data. Variant chr19-40608301-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40608301-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00293 (447/152316) while in subpopulation AFR AF= 0.0103 (427/41556). AF 95% confidence interval is 0.00947. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042545.2	c.1238G>A	p.Gly413Asp	missense_variant	8/30	ENST00000396819.8
LTBP4	NM_001042544.1	c.1439G>A	p.Gly480Asp	missense_variant	11/33
LTBP4	NM_003573.2	c.1328G>A	p.Gly443Asp	missense_variant	11/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000396819.8	c.1238G>A	p.Gly413Asp	missense_variant	8/30	1	NM_001042545.2	P3

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000713 AC: 177 AN: 248238 Hom.: 1 AF XY: 0.000534 AC XY: 72 AN XY: 134886

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1461476 Hom.: 1 Cov.: 31 AF XY: 0.000267 AC XY: 194 AN XY: 727034

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00293 AC: 447 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74480

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000952 Hom.: 1

Bravo AF: 0.00304

ESP6500AA AF: 0.00974 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000819 AC: 99

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

LTBP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2019

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	0.095
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.052	T;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.40	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.012	.;B;.
Vest4		0.31
MVP		0.25
MPC		0.46
ClinPred		0.0058	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.46

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: rs114749335; hg19: chr19-41114207;