rs137854856

Variant names:

• chr14-74508727-C-T
• rs137854856
• NM_000428.3:c.3529G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-74508727-C-T
• chr14-74508727-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000428.3(LTBP2):​c.3529G>A​(p.Val1177Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTBP2 NM_000428.3 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.453
• Publications: 6 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 14-74508727-C-T is Pathogenic according to our data. Variant chr14-74508727-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37093.Status of the report is no_assertion_criteria_provided, 0 stars.

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.3529G>A	p.Val1177Met	missense splice_region	Exon 24 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.3529G>A	p.Val1177Met	missense splice_region	Exon 24 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.3427G>A	p.Val1143Met	missense splice_region	Exon 23 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.3529G>A	p.Val1177Met	missense splice_region	Exon 24 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Weill-Marchesani syndrome 1 (1)
1	-	-	Weill-Marchesani syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L
PhyloP100		-0.45
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Benign	0.10	T
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.66		Gain of catalytic residue at V1173 (P = 0)
MVP		0.63
MPC		0.18
ClinPred		0.41	T
GERP RS		-1.3
Varity_R		0.11
gMVP		0.22
Mutation Taster		=90/10	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137854856; hg19: chr14-74975430;