14-74498200-T-C

Position:

• chr14-74498200-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_000428.3(LTBP2):​c.*2684A>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 0.00989 in 175,228 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (1 hom.)
• Consequence: LTBP2 NM_000428.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.86

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 14-74498200-T-C is Benign according to our data. Variant chr14-74498200-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 886320.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00995 (1516/152320) while in subpopulation NFE AF= 0.0144 (979/68032). AF 95% confidence interval is 0.0136. There are 15 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.*2684A>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.*2684A>G		3_prime_UTR_variant	36/36	1	NM_000428.3	ENSP00000261978	P1

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1515 AN: 152202 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00947 AC: 217 AN: 22908 Hom.: 1 Cov.: 0 AF XY: 0.0104 AC XY: 110 AN XY: 10566

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.00625

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.00163

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0714

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00995 AC: 1516 AN: 152320 Hom.: 15 Cov.: 33 AF XY: 0.0101 AC XY: 752 AN XY: 74484

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0124 Hom.: 4

Bravo AF: 0.00853

Asia WGS AF: 0.00722 AC: 25 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LTBP2: BS1, BS2 -

Glaucoma 3, primary congenital, D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.90

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: rs74384554; hg19: chr14-74964903;