dbSNP rs985929702: LTBP1:p.Gly92Asp (chr2-32947599-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_206943.4(LTBP1):c.275G>A(p.Gly92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,311,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

LTBP1
NM_206943.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.587

Publications

1 publications found

Variant links:

Genes affected

LTBP1 (HGNC:6714): (latent transforming growth factor beta binding protein 1) The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

LTBP1 Gene-Disease associations (from GenCC):

cutis laxa, autosomal recessive, type 2E
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

LTBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.11618689).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206943.4. 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
	LTBP1	NM_206943.4	MANE Select	c.275G>A	p.Gly92Asp	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.275G>A	p.Gly92Asp	missense	Exon 1 of 34	NP_001381834.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP1	ENST00000404816.7	TSL:5 MANE Select	c.275G>A	p.Gly92Asp	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
LTBP1	ENST00000929169.1		c.275G>A	p.Gly92Asp	missense	Exon 1 of 34	ENSP00000599228.1
LTBP1	ENST00000954823.1		c.275G>A	p.Gly92Asp	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes

AF:

0.0000861

AC:

AN:

151052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000192

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000154

AC:

AN:

6496

AF XY:

0.000240

show subpopulations

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:

0.000398

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000355

AC:

412

AN:

1160874

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

183

AN XY:

564226

show subpopulations

African (AFR)

AF:

0.0000439

AC:

AN:

22792

American (AMR)

AF:

0.00

AC:

AN:

9196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15192

East Asian (EAS)

AF:

0.00

AC:

AN:

25882

South Asian (SAS)

AF:

0.00

AC:

AN:

41838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3172

European-Non Finnish (NFE)

AF:

0.000412

AC:

399

AN:

967656

Other (OTH)

AF:

0.000259

AC:

AN:

46416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.0000861

AC:

AN:

151052

Hom.:

Cov.:

AF XY:

0.0000950

AC XY:

AN XY:

73720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41294

American (AMR)

AF:

0.00

AC:

AN:

15158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000192

AC:

AN:

67676

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.0000945

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.094

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.47

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.81

PhyloP100

0.59

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.21

REVEL

Benign

0.11

Sift

Benign

0.47

Sift4G

Benign

0.99

Vest4

0.14

MutPred

0.21

Loss of methylation at K89 (P = 0.0747)

MVP

0.18

MPC

2.2

ClinPred

0.021

GERP RS

1.0

Varity_R

0.065

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over