Genetic Variant LTBP4:c.17-2227C>T (chr19-40596970-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_003573.2(LTBP4):c.17-2227C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 151,918 control chromosomes in the GnomAD database, including 2,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.18 ( 2610 hom., cov: 30)

Consequence

LTBP4
NM_003573.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.575

Publications

2 publications found

Variant links:

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LTBP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 19-40596970-C-T is Benign according to our data. Variant chr19-40596970-C-T is described in ClinVar as Benign. ClinVar VariationId is 668714.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003573.2. 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
	LTBP4	NM_003573.2		c.17-2227C>T		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LTBP4	ENST00000204005.13	TSL:1	c.17-2227C>T	intron	N/A	ENSP00000204005.10	A0A0C4DH07
LTBP4	ENST00000599016.5	TSL:3	n.17-2227C>T	intron	N/A	ENSP00000482179.1	A0A087WYX7
LTBP4	ENST00000600026.5	TSL:3	n.17-2227C>T	intron	N/A	ENSP00000483230.1	A0A087X0A7

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27449

AN:

151796

Hom.:

2614

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.0945

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.179

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.181

AC:

27446

AN:

151918

Hom.:

2610

Cov.:

AF XY:

0.185

AC XY:

13722

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.166

AC:

6865

AN:

41476

American (AMR)

AF:

0.149

AC:

2269

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

728

AN:

3468

East Asian (EAS)

AF:

0.277

AC:

1414

AN:

5108

South Asian (SAS)

AF:

0.258

AC:

1242

AN:

4806

European-Finnish (FIN)

AF:

0.249

AC:

2626

AN:

10558

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.174

AC:

11786

AN:

67910

Other (OTH)

AF:

0.177

AC:

373

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1096

2191

3287

4382

5478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.187

Hom.:

333

Bravo

AF:

0.173

Asia WGS

AF:

0.235

AC:

817

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.3

(source)

DANN

Benign

0.91

PhyloP100

0.57

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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