19-40598954-G-T

Variant names:

• chr19-40598954-G-T
• rs1864074
• ENST00000308370.11:c.147-243G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001042544.1(LTBP4):​c.147-243G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,990 control chromosomes in the GnomAD database, including 21,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (21000 hom., cov: 32)
• Consequence: LTBP4 NM_001042544.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.227
• Publications: 14 publications found

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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-40598954-G-T is Benign according to our data. Variant chr19-40598954-G-T is described in ClinVar as Benign. ClinVar VariationId is 1286634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042544.1. 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_001042544.1		c.147-243G>T		intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.17-243G>T		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000308370.11	TSL:1	c.147-243G>T		intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.17-243G>T		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000594537.2	TSL:5	n.95-243G>T		intron	N/A	ENSP00000480629.1	A0A087WWZ7

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76164 AN: 151872 Hom.: 20962 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.502 AC: 76260 AN: 151990 Hom.: 21000 Cov.: 32 AF XY: 0.503 AC XY: 37375 AN XY: 74292

African (AFR) AF: 0.740 AC: 30684 AN: 41478

American (AMR) AF: 0.383 AC: 5850 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1932 AN: 3468

East Asian (EAS) AF: 0.398 AC: 2055 AN: 5166

South Asian (SAS) AF: 0.536 AC: 2589 AN: 4828

European-Finnish (FIN) AF: 0.465 AC: 4904 AN: 10538

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26792 AN: 67952

Other (OTH) AF: 0.471 AC: 990 AN: 2102

Alfa AF: 0.421 Hom.: 16544

Bravo AF: 0.504

Asia WGS AF: 0.492 AC: 1709 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	6.6
DANN	Benign	0.31
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs1864074; hg19: chr19-41104860;