rs117800773

Positions:

• chr14-74503992-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000428.3(LTBP2):​c.4516G>A​(p.Val1506Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,118 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: LTBP2 NM_000428.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010105163).
• BP6: Variant 14-74503992-C-T is Benign according to our data. Variant chr14-74503992-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 314272.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP2	NM_000428.3	c.4516G>A	p.Val1506Met	missense_variant	31/36	ENST00000261978.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP2	ENST00000261978.9	c.4516G>A	p.Val1506Met	missense_variant	31/36	1	NM_000428.3	P1
LTBP2	ENST00000556690.5	c.4384G>A	p.Val1462Met	missense_variant	30/35	5
LTBP2	ENST00000553939.5	c.4516G>A	p.Val1506Met	missense_variant, NMD_transcript_variant	31/36	5

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00145 AC: 364 AN: 251048 Hom.: 0 AF XY: 0.00150 AC XY: 203 AN XY: 135774

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00214 AC: 3132 AN: 1461812 Hom.: 6 Cov.: 32 AF XY: 0.00203 AC XY: 1474 AN XY: 727206

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74460

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Weill-Marchesani syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Weill-Marchesani syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 01, 2017

LTBP2 NM_000428.2 exon31 p.Val1506Met (c.4516G>A): This variant has not been reported in the literature but is present in 0.2% (245/126544) of European chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs117800773). This variant is present in ClinVar (Variation ID:314272). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Glaucoma 3, primary congenital, D Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Glaucoma 3, primary congenital, D;C3538951:Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma;C3553785:Weill-Marchesani syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

LTBP2 NM_000428.2 exon31 p.Val1506Met (c.4516G>A): This variant has not been reported in the literature but is present in 0.2% (245/126544) of European chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs117800773). This variant is present in ClinVar (Variation ID:314272). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

LTBP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely 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	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.62	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.26
Sift	Benign	0.081	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.41	B;.
Vest4		0.37
MVP		0.71
MPC		0.19
ClinPred		0.028	T
GERP RS		5.0
Varity_R		0.048
gMVP		0.69

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: rs117800773; hg19: chr14-74970695; COSMIC: COSV56209721; COSMIC: COSV56209721;