rs137854856

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000428.3(LTBP2):​c.3529G>C​(p.Val1177Leu) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1177M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTBP2 NM_000428.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 3

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14197922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	Exon 24 of 36	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	Exon 24 of 36	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	Exon 24 of 35	5		ENSP00000451477.1
LTBP2	ENST00000556206.1	c.325G>C	p.Val109Leu	missense_variant, splice_region_variant	Exon 4 of 6	5		ENSP00000450668.1
LTBP2	ENST00000553939.5	n.3529G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 36	5		ENSP00000452110.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251088 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.4
DANN	Benign	0.79
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		-0.45
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.053	B;.
Vest4		0.21
MutPred		0.65		Gain of catalytic residue at M1181 (P = 0.0077);Gain of catalytic residue at M1181 (P = 0.0077);
MVP		0.43
MPC		0.14
ClinPred		0.065	T
GERP RS		-1.3
Varity_R		0.22
gMVP		0.20
Mutation Taster		=89/11	polymorphism

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;