14-74499011-G-C

Position:

• chr14-74499011-G-C

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.*1873C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 220,024 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (151 hom., cov: 33)
  • Exomes 𝑓: 0.041 (79 hom.)
• Consequence: LTBP2 NM_000428.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.426

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 14-74499011-G-C is Benign according to our data. Variant chr14-74499011-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 884352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.*1873C>G		3_prime_UTR_variant	36/36	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.*1873C>G		3_prime_UTR_variant	36/36	1	NM_000428.3	ENSP00000261978	P1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6086 AN: 152186 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0517

Gnomad OTH AF: 0.0554

GnomAD4 exome AF: 0.0411 AC: 2784 AN: 67720 Hom.: 79 Cov.: 0 AF XY: 0.0400 AC XY: 1255 AN XY: 31336

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.0526

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.0511

GnomAD4 genome AF: 0.0399 AC: 6083 AN: 152304 Hom.: 151 Cov.: 33 AF XY: 0.0390 AC XY: 2904 AN XY: 74458

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0520

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0281

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0517

Gnomad4 OTH AF: 0.0548

Alfa AF: 0.0485 Hom.: 23

Bravo AF: 0.0408

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.4
DANN	Benign	0.86

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: rs77847288; hg19: chr14-74965714;