rs149115544

chr11-65539637-A-G

Variant summary

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

The NM_001130144.3(LTBP3):c.3548-9T>C 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 0.00189 in 1,608,204 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (90 hom.)
• Consequence: LTBP3 NM_001130144.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001095
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.415

Genes affected

LTBP3 (HGNC:6716): (latent transforming growth factor beta binding protein 3) The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-65539637-A-G is Benign according to our data. Variant chr11-65539637-A-G is described in ClinVar as [Benign]. Clinvar id is 532698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP3	NM_001130144.3	c.3548-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000301873.11
LTBP3	NM_001164266.1	c.3056-9T>C		splice_polypyrimidine_tract_variant, intron_variant
LTBP3	NM_021070.4	c.3407-9T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP3	ENST00000301873.11	c.3548-9T>C		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001130144.3	P1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 393 AN: 151992 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0661

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00562 AC: 1335 AN: 237460 Hom.: 48 AF XY: 0.00530 AC XY: 686 AN XY: 129342

Gnomad AFR exome AF: 0.000335

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0712

Gnomad SAS exome AF: 0.00159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000559

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00182 AC: 2643 AN: 1456098 Hom.: 90 Cov.: 38 AF XY: 0.00178 AC XY: 1292 AN XY: 724166

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0505

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152106 Hom.: 12 Cov.: 33 AF XY: 0.00308 AC XY: 229 AN XY: 74370

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0665

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00329

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

LTBP3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.0
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.030		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: rs149115544; hg19: chr11-65307108;