rs61738025

Positions:

• chr14-74552299-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000428.3(LTBP2):​c.1287G>A​(p.Leu429=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 1,613,186 control chromosomes in the GnomAD database, including 2,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (339 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2403 hom.)
• Consequence: LTBP2 NM_000428.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.751

Genes affected

LTBP2 (HGNC:6715): (latent transforming growth factor beta binding protein 2) The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 14-74552299-C-T is Benign according to our data. Variant chr14-74552299-C-T is described in ClinVar as [Benign]. Clinvar id is 256096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74552299-C-T is described in Lovd as [Benign]. Variant chr14-74552299-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP2	NM_000428.3	c.1287G>A	p.Leu429=	synonymous_variant	6/36	ENST00000261978.9
LOC124903346	XR_007064265.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP2	ENST00000261978.9	c.1287G>A	p.Leu429=	synonymous_variant	6/36	1	NM_000428.3	P1
	ENST00000554552.1	n.119C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9704 AN: 152168 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.0801

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0702

GnomAD3 exomes AF: 0.0597 AC: 14854 AN: 249004 Hom.: 454 AF XY: 0.0587 AC XY: 7932 AN XY: 135018

Gnomad AFR exome AF: 0.0874

Gnomad AMR exome AF: 0.0584

Gnomad ASJ exome AF: 0.0753

Gnomad EAS exome AF: 0.0862

Gnomad SAS exome AF: 0.0526

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0616

GnomAD4 exome AF: 0.0552 AC: 80634 AN: 1460900 Hom.: 2403 Cov.: 38 AF XY: 0.0553 AC XY: 40204 AN XY: 726762

Gnomad4 AFR exome AF: 0.0847

Gnomad4 AMR exome AF: 0.0608

Gnomad4 ASJ exome AF: 0.0796

Gnomad4 EAS exome AF: 0.0963

Gnomad4 SAS exome AF: 0.0528

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0519

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0637 AC: 9702 AN: 152286 Hom.: 339 Cov.: 32 AF XY: 0.0636 AC XY: 4734 AN XY: 74474

Gnomad4 AFR AF: 0.0835

Gnomad4 AMR AF: 0.0676

Gnomad4 ASJ AF: 0.0937

Gnomad4 EAS AF: 0.0803

Gnomad4 SAS AF: 0.0448

Gnomad4 FIN AF: 0.0520

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0591 Hom.: 161

Bravo AF: 0.0671

Asia WGS AF: 0.0690 AC: 239 AN: 3478

EpiCase AF: 0.0556

EpiControl AF: 0.0573

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Weill-Marchesani syndrome 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. -

Glaucoma 3, primary congenital, D 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
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61738025; hg19: chr14-75019002; COSMIC: COSV56211205;