11-65540929-G-T

Variant names:

• chr11-65540929-G-T
• rs145041278
• NM_001130144.3:c.2919C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130144.3(LTBP3):​c.2919C>A​(p.Asp973Glu) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D973N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 2 publications found

Genes affected

LTBP3 (HGNC:6716): (latent transforming growth factor beta binding protein 3) The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

LTBP3 Gene-Disease associations (from GenCC):

• brachyolmia-amelogenesis imperfecta syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• geleophysic dysplasia 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24298576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP3	NM_001130144.3	c.2919C>A	p.Asp973Glu	missense_variant	Exon 21 of 28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4	c.2919C>A	p.Asp973Glu	missense_variant	Exon 21 of 27		NP_066548.2
LTBP3	NM_001164266.1	c.2568C>A	p.Asp856Glu	missense_variant	Exon 21 of 27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11	c.2919C>A	p.Asp973Glu	missense_variant	Exon 21 of 28	2	NM_001130144.3	ENSP00000301873.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248126 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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.068	.;T;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	-0.45	N;N;.;.
PhyloP100		-1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.0	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.57	T;T;T;.
Polyphen		0.98	D;D;P;D
Vest4		0.45
MutPred		0.33		Gain of catalytic residue at D973 (P = 0.0958);Gain of catalytic residue at D973 (P = 0.0958);.;.;
MVP		0.92
ClinPred		0.84	D
GERP RS		-2.7
PromoterAI		-0.072	Neutral
Varity_R		0.051
gMVP		0.56
Mutation Taster		=275/25	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: rs145041278; hg19: chr11-65308400;