chr11-65539105-G-A

Variant names:

• chr11-65539105-G-A
• rs1395508528
• NM_001130144.3:c.3887C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130144.3(LTBP3):​c.3887C>T​(p.Ala1296Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,309,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1296T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.95
• Publications: 0 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057642072).

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.3887C>T	p.Ala1296Val	missense	Exon 28 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.3746C>T	p.Ala1249Val	missense	Exon 27 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.3395C>T	p.Ala1132Val	missense	Exon 27 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.3887C>T	p.Ala1296Val	missense	Exon 28 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.3746C>T	p.Ala1249Val	missense	Exon 27 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*3391C>T		non_coding_transcript_exon	Exon 27 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000102 AC: 1 AN: 97810 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: 0.000161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1309844 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 642894

African (AFR) AF: 0.00 AC: 0 AN: 26294

American (AMR) AF: 0.00 AC: 0 AN: 29110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22608

East Asian (EAS) AF: 0.0000343 AC: 1 AN: 29160

South Asian (SAS) AF: 0.00 AC: 0 AN: 73720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 9.65e-7 AC: 1 AN: 1036538

Other (OTH) AF: 0.00 AC: 0 AN: 53352

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.27	N
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.094
MutPred		0.32		Loss of glycosylation at S1291 (P = 0.1653)
MVP		0.76
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.075
gMVP		0.41
Mutation Taster		=85/15	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: rs1395508528; hg19: chr11-65306576;