14-74508727-C-T

Position:

• chr14-74508727-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 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 id is 37093.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-74508727-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.3529G>A	p.Val1177Met	missense_variant, splice_region_variant	24/36	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.3529G>A	p.Val1177Met	missense_variant, splice_region_variant	24/36	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.3529G>A	p.Val1177Met	missense_variant, splice_region_variant	24/35	5		ENSP00000451477.1
LTBP2	ENST00000556206.1	c.325G>A	p.Val109Met	missense_variant, splice_region_variant	4/6	5		ENSP00000450668.1
LTBP2	ENST00000553939.5	n.3529G>A		splice_region_variant, non_coding_transcript_exon_variant	24/36	5		ENSP00000452110.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Weill-Marchesani syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Elahi Laboratory, University of Tehran

-

- -

Weill-Marchesani syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.10	T;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.99	D;.
Vest4		0.39
MutPred		0.66		Gain of catalytic residue at V1173 (P = 0);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

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: rs137854856; hg19: chr14-74975430;