11-65539117-C-T

Position:

• chr11-65539117-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001130144.3(LTBP3):​c.3875G>A​(p.Arg1292His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,321,598 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28505605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP3	NM_001130144.3	c.3875G>A	p.Arg1292His	missense_variant	28/28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4	c.3734G>A	p.Arg1245His	missense_variant	27/27		NP_066548.2
LTBP3	NM_001164266.1	c.3383G>A	p.Arg1128His	missense_variant	27/27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11	c.3875G>A	p.Arg1292His	missense_variant	28/28	2	NM_001130144.3	ENSP00000301873	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000287 AC: 3 AN: 104442 Hom.: 0 AF XY: 0.0000172 AC XY: 1 AN XY: 58204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.000289

Gnomad SAS 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: 0.0000136 AC: 18 AN: 1321598 Hom.: 0 Cov.: 31 AF XY: 0.00000924 AC XY: 6 AN XY: 649368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000673

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1292 of the LTBP3 protein (p.Arg1292His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LTBP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1427542). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.3875G>A (p.R1292H) alteration is located in exon 28 (coding exon 28) of the LTBP3 gene. This alteration results from a G to A substitution at nucleotide position 3875, causing the arginine (R) at amino acid position 1292 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.048	D;D;T;T;T
Sift4G	Benign	0.067	T;T;T;T;T
Polyphen		1.0	D;D;.;.;D
Vest4		0.43
MutPred		0.41		.;Loss of MoRF binding (P = 0.0108);.;.;.;
MVP		0.80
ClinPred		0.39	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.71

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: rs1282350856; hg19: chr11-65306588; COSMIC: COSV54211512; COSMIC: COSV54211512;