11-65546806-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001130144.3(LTBP3):ā€‹c.2222C>Gā€‹(p.Ala741Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,604,476 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.010 ( 19 hom., cov: 32)
Exomes š‘“: 0.0066 ( 99 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.331
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0049988627).
BP6
Variant 11-65546806-G-C is Benign according to our data. Variant chr11-65546806-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 532699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0802 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LTBP3NM_001130144.3 linkc.2222C>G p.Ala741Gly missense_variant 15/28 ENST00000301873.11 NP_001123616.1 Q9NS15-1Q8WYU6
LTBP3NM_021070.4 linkc.2222C>G p.Ala741Gly missense_variant 15/27 NP_066548.2 Q9NS15-2Q8WYU6
LTBP3NM_001164266.1 linkc.1871C>G p.Ala624Gly missense_variant 15/27 NP_001157738.1 Q9NS15B9EG76Q8WYU6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LTBP3ENST00000301873.11 linkc.2222C>G p.Ala741Gly missense_variant 15/282 NM_001130144.3 ENSP00000301873.5 Q9NS15-1

Frequencies

GnomAD3 genomes
AF:
0.0103
AC:
1568
AN:
152174
Hom.:
19
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0180
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0103
Gnomad ASJ
AF:
0.0375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.0886
Gnomad NFE
AF:
0.00661
Gnomad OTH
AF:
0.0210
GnomAD3 exomes
AF:
0.00790
AC:
1879
AN:
237826
Hom.:
15
AF XY:
0.00768
AC XY:
1002
AN XY:
130458
show subpopulations
Gnomad AFR exome
AF:
0.0183
Gnomad AMR exome
AF:
0.00753
Gnomad ASJ exome
AF:
0.0351
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00268
Gnomad FIN exome
AF:
0.000387
Gnomad NFE exome
AF:
0.00737
Gnomad OTH exome
AF:
0.0184
GnomAD4 exome
AF:
0.00665
AC:
9653
AN:
1452188
Hom.:
99
Cov.:
37
AF XY:
0.00678
AC XY:
4898
AN XY:
722722
show subpopulations
Gnomad4 AFR exome
AF:
0.0179
Gnomad4 AMR exome
AF:
0.00832
Gnomad4 ASJ exome
AF:
0.0351
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00284
Gnomad4 FIN exome
AF:
0.000786
Gnomad4 NFE exome
AF:
0.00565
Gnomad4 OTH exome
AF:
0.0120
GnomAD4 genome
AF:
0.0103
AC:
1563
AN:
152288
Hom.:
19
Cov.:
32
AF XY:
0.00965
AC XY:
719
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0179
Gnomad4 AMR
AF:
0.0103
Gnomad4 ASJ
AF:
0.0375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.000471
Gnomad4 NFE
AF:
0.00662
Gnomad4 OTH
AF:
0.0208
Alfa
AF:
0.00830
Hom.:
5
Bravo
AF:
0.0118
ESP6500AA
AF:
0.0155
AC:
68
ESP6500EA
AF:
0.00701
AC:
60
ExAC
AF:
0.00715
AC:
864
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0117
EpiControl
AF:
0.0104

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 13, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.30
.;T;.;T;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.031
T;T;T;T;T
MetaRNN
Benign
0.0050
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.79
N;N;.;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.6
N;N;N;N;N
REVEL
Benign
0.076
Sift
Benign
0.24
T;T;T;T;T
Sift4G
Benign
0.37
T;T;T;.;T
Polyphen
0.089
B;B;B;B;.
Vest4
0.35
MVP
0.23
ClinPred
0.019
T
GERP RS
4.1
Varity_R
0.16
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148780991; hg19: chr11-65314277; COSMIC: COSV57240009; COSMIC: COSV57240009; API