14-74498927-T-C

Position:

• chr14-74498927-T-C

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.*1957A>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 0.0251 in 225,244 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (127 hom., cov: 33)
  • Exomes 𝑓: 0.015 (25 hom.)
• Consequence: LTBP2 NM_000428.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.125

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=-0.49).
• BP6: Variant 14-74498927-T-C is Benign according to our data. Variant chr14-74498927-T-C is described in ClinVar as [Benign]. Clinvar id is 314245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.*1957A>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.*1957A>G		3_prime_UTR_variant	36/36	1	NM_000428.3	ENSP00000261978	P1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4541 AN: 152230 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0253

GnomAD4 exome AF: 0.0151 AC: 1100 AN: 72896 Hom.: 25 Cov.: 0 AF XY: 0.0148 AC XY: 498 AN XY: 33608

Gnomad4 AFR exome AF: 0.0739

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.00155

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0299 AC: 4555 AN: 152348 Hom.: 127 Cov.: 33 AF XY: 0.0292 AC XY: 2174 AN XY: 74506

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0209 Hom.: 10

Bravo AF: 0.0322

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: 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 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 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 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.8
DANN	Benign	0.87

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: rs73296215; hg19: chr14-74965630;