19-40608363-T-A

Position:

• chr19-40608363-T-A

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.1300T>A​(p.Ser434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00976 in 1,612,550 control chromosomes in the GnomAD database, including 763 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 0.041 (376 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (387 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.25

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=0.0013553202).
• BP6: Variant 19-40608363-T-A is Benign according to our data. Variant chr19-40608363-T-A is described in ClinVar as [Benign]. Clinvar id is 178780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40608363-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.1300T>A	p.Ser434Thr	missense_variant	8/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1501T>A	p.Ser501Thr	missense_variant	11/33		NP_001036009.1
LTBP4	NM_003573.2	c.1390T>A	p.Ser464Thr	missense_variant	11/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.1300T>A	p.Ser434Thr	missense_variant	8/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6302 AN: 152202 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00931

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0123 AC: 3013 AN: 245808 Hom.: 153 AF XY: 0.00989 AC XY: 1320 AN XY: 133496

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.00835

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000297

Gnomad FIN exome AF: 0.00806

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00888

GnomAD4 exome AF: 0.00646 AC: 9431 AN: 1460230 Hom.: 387 Cov.: 31 AF XY: 0.00587 AC XY: 4264 AN XY: 726190

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.00916

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000419

Gnomad4 FIN exome AF: 0.00778

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0414 AC: 6311 AN: 152320 Hom.: 376 Cov.: 32 AF XY: 0.0408 AC XY: 3041 AN XY: 74502

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00931

Gnomad4 NFE AF: 0.00270

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.00925 Hom.: 31

Bravo AF: 0.0474

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.127 AC: 509

ESP6500EA AF: 0.00241 AC: 20

ExAC AF: 0.0138 AC: 1663

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00405

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ser501Thr in exon 11 of LTBP4: This variant is not expected to have clinical sig nificance because it has been identified in 12.7% (509/4004) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34545902). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Benign	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.044	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.087
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.016	.;B;.
Vest4		0.12
MPC		0.31
ClinPred		0.000020	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.033
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34545902; hg19: chr19-41114269;