chr14-74555568-G-A

Position:

• chr14-74555568-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000428.3(LTBP2):​c.956C>T​(p.Pro319Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. P319Q) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: LTBP2 NM_000428.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.664

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10099614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.956C>T	p.Pro319Leu	missense_variant	4/36	ENST00000261978.9	NP_000419.1
LOC124903346	XR_007064265.1	n.99+3155G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.956C>T	p.Pro319Leu	missense_variant	4/36	1	NM_000428.3	ENSP00000261978	P1
	ENST00000554552.1	n.233+3155G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.096
Sift	Benign	0.11	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.34	B;.
Vest4		0.12
MutPred		0.33		Gain of catalytic residue at P316 (P = 0);Gain of catalytic residue at P316 (P = 0);
MVP		0.48
MPC		0.14
ClinPred		0.071	T
GERP RS		-0.039
Varity_R		0.083
gMVP		0.40

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: rs2304707; hg19: chr14-75022271;