11-65546806-G-C

Variant names:

• chr11-65546806-G-C
• rs148780991
• NM_001130144.3:c.2222C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130144.3(LTBP3):​c.2222C>G​(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A741V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (99 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.331
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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.2222C>G	p.Ala741Gly	missense	Exon 15 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.2222C>G	p.Ala741Gly	missense	Exon 15 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.1871C>G	p.Ala624Gly	missense	Exon 15 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.2222C>G	p.Ala741Gly	missense	Exon 15 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.2222C>G	p.Ala741Gly	missense	Exon 15 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*1867C>G		non_coding_transcript_exon	Exon 15 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1568 AN: 152174 Hom.: 19 Cov.: 32

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

GnomAD2 exomes AF: 0.00790 AC: 1879 AN: 237826 AF XY: 0.00768

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 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

African (AFR) AF: 0.0179 AC: 600 AN: 33452

American (AMR) AF: 0.00832 AC: 372 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 916 AN: 26110

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86242

European-Finnish (FIN) AF: 0.000786 AC: 35 AN: 44534

Middle Eastern (MID) AF: 0.0865 AC: 485 AN: 5604

European-Non Finnish (NFE) AF: 0.00565 AC: 6276 AN: 1111566

Other (OTH) AF: 0.0120 AC: 721 AN: 60276

GnomAD4 genome AF: 0.0103 AC: 1563 AN: 152288 Hom.: 19 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74472

African (AFR) AF: 0.0179 AC: 745 AN: 41552

American (AMR) AF: 0.0103 AC: 157 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.00662 AC: 450 AN: 68024

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.031	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.79	N
PhyloP100		0.33
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.076
Sift	Benign	0.24	T
Sift4G	Benign	0.37	T
Polyphen		0.089	B
Vest4		0.35
MVP		0.23
ClinPred		0.019	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.55
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

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