rs78258030

Variant names:

• chr14-74521898-G-A
• rs78258030
• NM_000428.3:c.2788+13C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000428.3(LTBP2):​c.2788+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,784 control chromosomes in the GnomAD database, including 823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (184 hom., cov: 33)
  • Exomes 𝑓: 0.019 (639 hom.)
• Consequence: LTBP2 NM_000428.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 14-74521898-G-A is Benign according to our data. Variant chr14-74521898-G-A is described in ClinVar as [Benign]. Clinvar id is 256098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74521898-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.2788+13C>T		intron_variant	Intron 17 of 35	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.2788+13C>T		intron_variant	Intron 17 of 35	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.2788+13C>T		intron_variant	Intron 17 of 34	5		ENSP00000451477.1
LTBP2	ENST00000553939.5	n.2788+13C>T		intron_variant	Intron 17 of 35	5		ENSP00000452110.1

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5323 AN: 152194 Hom.: 185 Cov.: 33

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0821

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0246 AC: 6182 AN: 251064 Hom.: 195 AF XY: 0.0269 AC XY: 3658 AN XY: 135750

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.00995

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.0828

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0187 AC: 27365 AN: 1461474 Hom.: 639 Cov.: 32 AF XY: 0.0205 AC XY: 14902 AN XY: 727054

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.0823

Gnomad4 FIN exome AF: 0.00813

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0349 AC: 5316 AN: 152310 Hom.: 184 Cov.: 33 AF XY: 0.0348 AC XY: 2591 AN XY: 74466

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0815

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0247 Hom.: 20

Bravo AF: 0.0354

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Weill-Marchesani syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.98
CADD	Benign	0.0050
DANN	Benign	0.34

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: rs78258030; hg19: chr14-74988601;