rs752311785

Variant names:

• chr11-65553814-C-T
• rs752311785
• NM_001130144.3:c.751G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001130144.3(LTBP3):​c.751G>A​(p.Glu251Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,561,526 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. E251G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: LTBP3 NM_001130144.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.16
• Publications: 3 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

ENSG00000302197 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18654111).

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.751G>A	p.Glu251Lys	missense	Exon 3 of 28	NP_001123616.1	Q9NS15-1
	LTBP3	NM_021070.4		c.751G>A	p.Glu251Lys	missense	Exon 3 of 27	NP_066548.2	Q9NS15-2
	LTBP3	NM_001164266.1		c.400G>A	p.Glu134Lys	missense	Exon 3 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.751G>A	p.Glu251Lys	missense	Exon 3 of 28	ENSP00000301873.5	Q9NS15-1
	LTBP3	ENST00000322147.8	TSL:1	c.751G>A	p.Glu251Lys	missense	Exon 3 of 27	ENSP00000326647.4	Q9NS15-2
	LTBP3	ENST00000528516.5	TSL:1	n.*396G>A		non_coding_transcript_exon	Exon 3 of 27	ENSP00000432350.1	E9PRF2

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151768 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000960 AC: 16 AN: 166588 AF XY: 0.0000876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 249 AN: 1409758 Hom.: 0 Cov.: 34 AF XY: 0.000168 AC XY: 117 AN XY: 698106

African (AFR) AF: 0.0000610 AC: 2 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 38842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 37824

South Asian (SAS) AF: 0.00 AC: 0 AN: 81656

European-Finnish (FIN) AF: 0.0000849 AC: 3 AN: 35316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.000217 AC: 237 AN: 1093400

Other (OTH) AF: 0.000119 AC: 7 AN: 58856

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151768 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74084

African (AFR) AF: 0.0000242 AC: 1 AN: 41296

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000687 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.33	N
REVEL	Uncertain	0.31
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.55	P
Vest4		0.35
MVP		0.86
ClinPred		0.13	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.32
Mutation Taster		=70/30	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: rs752311785; hg19: chr11-65321285; COSMIC: COSV57242150; COSMIC: COSV57242150;