rs61738025

Variant names:

• chr14-74552299-C-T
• rs61738025
• NM_000428.3:c.1287G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000428.3(LTBP2):​c.1287G>A​(p.Leu429Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 1,613,186 control chromosomes in the GnomAD database, including 2,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L429L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (339 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2403 hom.)
• Consequence: LTBP2 NM_000428.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.751
• Publications: 15 publications found

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]

LTBP2 Gene-Disease associations (from GenCC):

• glaucoma 3, primary congenital, D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Weill-Marchesani syndrome 3

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma secondary to spherophakia/ectopia lentis and megalocornea

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258425 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 14-74552299-C-T is Benign according to our data. Variant chr14-74552299-C-T is described in ClinVar as Benign. ClinVar VariationId is 256096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	NM_000428.3	MANE Select	c.1287G>A	p.Leu429Leu	synonymous	Exon 6 of 36	NP_000419.1	Q14767

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.1287G>A	p.Leu429Leu	synonymous	Exon 6 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.1287G>A	p.Leu429Leu	synonymous	Exon 6 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.1287G>A	p.Leu429Leu	synonymous	Exon 6 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9704 AN: 152168 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.0801

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0702

GnomAD2 exomes AF: 0.0597 AC: 14854 AN: 249004 AF XY: 0.0587

Gnomad AFR exome AF: 0.0874

Gnomad AMR exome AF: 0.0584

Gnomad ASJ exome AF: 0.0753

Gnomad EAS exome AF: 0.0862

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0616

GnomAD4 exome AF: 0.0552 AC: 80634 AN: 1460900 Hom.: 2403 Cov.: 38 AF XY: 0.0553 AC XY: 40204 AN XY: 726762

African (AFR) AF: 0.0847 AC: 2837 AN: 33480

American (AMR) AF: 0.0608 AC: 2718 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 2081 AN: 26136

East Asian (EAS) AF: 0.0963 AC: 3822 AN: 39700

South Asian (SAS) AF: 0.0528 AC: 4554 AN: 86258

European-Finnish (FIN) AF: 0.0565 AC: 2968 AN: 52536

Middle Eastern (MID) AF: 0.0955 AC: 551 AN: 5768

European-Non Finnish (NFE) AF: 0.0519 AC: 57667 AN: 1111928

Other (OTH) AF: 0.0569 AC: 3436 AN: 60374

GnomAD4 genome AF: 0.0637 AC: 9702 AN: 152286 Hom.: 339 Cov.: 32 AF XY: 0.0636 AC XY: 4734 AN XY: 74474

African (AFR) AF: 0.0835 AC: 3471 AN: 41564

American (AMR) AF: 0.0676 AC: 1034 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 325 AN: 3470

East Asian (EAS) AF: 0.0803 AC: 415 AN: 5170

South Asian (SAS) AF: 0.0448 AC: 216 AN: 4826

European-Finnish (FIN) AF: 0.0520 AC: 552 AN: 10620

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0516 AC: 3511 AN: 68012

Other (OTH) AF: 0.0695 AC: 147 AN: 2116

Alfa AF: 0.0591 Hom.: 161

Bravo AF: 0.0671

Asia WGS AF: 0.0690 AC: 239 AN: 3478

EpiCase AF: 0.0556

EpiControl AF: 0.0573

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Glaucoma 3, primary congenital, D (1)
-	-	1	not specified (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.95
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61738025; hg19: chr14-75019002; COSMIC: COSV56211205;