dbSNP rs779871744: LTBP3:p.Ter1304del (chr11-65539073-GGCGGCGTCA-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001130144.3(LTBP3):c.3910_*6delTGACGCCGC(p.Ter1304del) variant causes a stop lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000408 in 1,224,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LTBP3
NM_001130144.3 stop_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.85

Publications

0 publications found

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]

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

LTBP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-65539073-GGCGGCGTCA-G is Pathogenic according to our data. Variant chr11-65539073-GGCGGCGTCA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422699.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP3	NM_001130144.3	MANE Select	c.3910_*6delTGACGCCGC	p.Ter1304del	stop_lost conservative_inframe_deletion	Exon 28 of 28	NP_001123616.1	Q9NS15-1
LTBP3	NM_001130144.3	MANE Select	c.3910_*6delTGACGCCGC		3_prime_UTR	Exon 28 of 28	NP_001123616.1	Q9NS15-1
LTBP3	NM_021070.4		c.3769_*6delTGACGCCGC	p.Ter1257del	stop_lost conservative_inframe_deletion	Exon 27 of 27	NP_066548.2	Q9NS15-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.3910_*6delTGACGCCGC	p.Ter1304del	stop_lost conservative_inframe_deletion	Exon 28 of 28	ENSP00000301873.5	Q9NS15-1
LTBP3	ENST00000322147.8	TSL:1	c.3769_*6delTGACGCCGC	p.Ter1257del	stop_lost conservative_inframe_deletion	Exon 27 of 27	ENSP00000326647.4	Q9NS15-2
LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.3910_*6delTGACGCCGC		3_prime_UTR	Exon 28 of 28	ENSP00000301873.5	Q9NS15-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000408

AC:

AN:

1224798

Hom.:

AF XY:

0.00000671

AC XY:

AN XY:

596490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23350

American (AMR)

AF:

0.00

AC:

AN:

13356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18262

East Asian (EAS)

AF:

0.00

AC:

AN:

27504

South Asian (SAS)

AF:

0.00

AC:

AN:

60074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3492

European-Non Finnish (NFE)

AF:

0.00000501

AC:

AN:

998634

Other (OTH)

AF:

0.00

AC:

AN:

49360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brachyolmia-amelogenesis imperfecta syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=109/91

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over