rs137854856

chr14-74508727-C-Gchr14-74508727-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/20 in silico tools predict a benign outcome for this variant. 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

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 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 id 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/exons	MANE	UniProt
LTBP2	NM_000428.3	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	24/36	ENST00000261978.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP2	ENST00000261978.9	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	24/36	1	NM_000428.3	P1
LTBP2	ENST00000556690.5	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant	24/35	5
LTBP2	ENST00000556206.1	c.328G>C	p.Val110Leu	missense_variant, splice_region_variant	4/6	5
LTBP2	ENST00000553939.5	c.3529G>C	p.Val1177Leu	missense_variant, splice_region_variant, NMD_transcript_variant	24/36	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251088 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135768

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 SAS 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;.
MutationTaster	Benign	1.0	N;N
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

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;