Genetic Variant NM_206943.4:c.88T>C (chr2-32947412-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_206943.4(LTBP1):c.88T>C(p.Tyr30His) variant causes a missense change. The variant allele was found at a frequency of 0.0000349 in 1,432,722 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 (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LTBP1
NM_206943.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3074682).

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.88T>C	p.Tyr30His	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.88T>C	p.Tyr30His	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.88T>C	p.Tyr30His	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
LTBP1	ENST00000929169.1		c.88T>C	p.Tyr30His	missense	Exon 1 of 34	ENSP00000599228.1
LTBP1	ENST00000954823.1		c.88T>C	p.Tyr30His	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes

AF:

0.0000528

AC:

AN:

151524

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000151

AC:

AN:

66428

AF XY:

0.0000258

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:

0.0000407

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1281198

Hom.:

Cov.:

AF XY:

0.0000412

AC XY:

AN XY:

631116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25846

American (AMR)

AF:

0.00

AC:

AN:

22596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22016

East Asian (EAS)

AF:

0.00

AC:

AN:

27190

South Asian (SAS)

AF:

0.00

AC:

AN:

68664

European-Finnish (FIN)

AF:

0.0000314

AC:

AN:

31890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3740

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

1026882

Other (OTH)

AF:

0.0000382

AC:

AN:

52374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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

AF:

0.0000528

AC:

AN:

151524

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41338

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.000142

Hom.:

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions

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

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.90

PhyloP100

3.6

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.43

REVEL

Uncertain

0.51

Sift

Benign

0.16

Sift4G

Uncertain

0.027

Vest4

0.31

MutPred

0.54

Gain of disorder (P = 0.0191)

MVP

0.24

MPC

2.1

ClinPred

0.43

GERP RS

3.4

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.14

gMVP

0.63

Mutation Taster

=88/12

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