11-65539090-C-T

Variant names:

• chr11-65539090-C-T
• rs1239972478
• NM_001130144.3:c.3902G>A

Variant summary

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

The NM_001130144.3(LTBP3):​c.3902G>A​(p.Arg1301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,427,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R1301R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.3902G>A	p.Arg1301His	missense	Exon 28 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.3761G>A	p.Arg1254His	missense	Exon 27 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.3410G>A	p.Arg1137His	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.3902G>A	p.Arg1301His	missense	Exon 28 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.3761G>A	p.Arg1254His	missense	Exon 27 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*3406G>A		non_coding_transcript_exon	Exon 27 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151852 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000235 AC: 30 AN: 1276058 Hom.: 0 Cov.: 31 AF XY: 0.0000144 AC XY: 9 AN XY: 624652

African (AFR) AF: 0.00 AC: 0 AN: 25220

American (AMR) AF: 0.00 AC: 0 AN: 22458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21292

East Asian (EAS) AF: 0.00 AC: 0 AN: 28250

South Asian (SAS) AF: 0.00 AC: 0 AN: 69424

European-Finnish (FIN) AF: 0.0000604 AC: 2 AN: 33140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.0000274 AC: 28 AN: 1020718

Other (OTH) AF: 0.00 AC: 0 AN: 51760

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74186

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000447 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.46		Loss of MoRF binding (P = 0.0099)
MVP		0.82
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.77
Mutation Taster		=62/38	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: rs1239972478; hg19: chr11-65306561;