11-65554255-C-G

Variant names:

• chr11-65554255-C-G
• rs373381192
• NM_001130144.3:c.457G>C

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.457G>C​(p.Gly153Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. G153S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Acromicric dysplasia

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302197 (HGNC:):

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=0.115781575).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130144.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	NM_001130144.3	MANE Select	c.457G>C	p.Gly153Arg	missense	Exon 2 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.457G>C	p.Gly153Arg	missense	Exon 2 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.106G>C	p.Gly36Arg	missense	Exon 2 of 27	NP_001157738.1	Q9NS15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.457G>C	p.Gly153Arg	missense	Exon 2 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.457G>C	p.Gly153Arg	missense	Exon 2 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*102G>C		non_coding_transcript_exon	Exon 2 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229956 AF XY: 0.00000784

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457476 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725082

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111024

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.13
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.39
MutPred		0.28		Loss of glycosylation at P156 (P = 0.1784)
MVP		0.76
ClinPred		0.040	T
GERP RS		-2.1
Varity_R		0.057
gMVP		0.33
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs373381192; hg19: chr11-65321726;