rs147282006

chr14-74536017-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000428.3(LTBP2):c.1790-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,610,602 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 33)
  • Exomes 𝑓: 0.012 (125 hom.)
• Consequence: LTBP2 NM_000428.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03

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=-0.88).
• BP6: Variant 14-74536017-C-T is Benign according to our data. Variant chr14-74536017-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74536017-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00843 (1283/152266) while in subpopulation NFE AF= 0.0132 (899/68008). AF 95% confidence interval is 0.0125. There are 11 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP2	NM_000428.3	c.1790-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261978.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP2	ENST00000261978.9	c.1790-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000428.3	P1
LTBP2	ENST00000556690.5	c.1790-17G>A		splice_polypyrimidine_tract_variant, intron_variant		5
LTBP2	ENST00000553939.5	c.1790-17G>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5
LTBP2	ENST00000557425.1	n.514-17G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 1284 AN: 152148 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00925 AC: 2322 AN: 250988 Hom.: 20 AF XY: 0.00906 AC XY: 1230 AN XY: 135718

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.0117 AC: 17121 AN: 1458336 Hom.: 125 Cov.: 31 AF XY: 0.0114 AC XY: 8239 AN XY: 725776

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.00843 AC: 1283 AN: 152266 Hom.: 11 Cov.: 33 AF XY: 0.00826 AC XY: 615 AN XY: 74442

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0116 Hom.: 1

Bravo AF: 0.00669

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.21
Dann	Benign	0.63

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: rs147282006; hg19: chr14-75002720;