19-40597348-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The ENST00000308370.11(LTBP4):c.114C>A(p.Val38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,523,686 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: LTBP4 ENST00000308370.11 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.670

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-40597348-C-A is Benign according to our data. Variant chr19-40597348-C-A is described in ClinVar as [Benign]. Clinvar id is 3035573.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00232 (353/152282) while in subpopulation AFR AF= 0.00804 (334/41556). AF 95% confidence interval is 0.00733. There are 3 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042544.1	c.114C>A	p.Val38=	synonymous_variant	1/33
LTBP4	NM_003573.2	c.17-1849C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000308370.11	c.114C>A	p.Val38=	synonymous_variant	1/33	1		A2
LTBP4	ENST00000204005.13	c.17-1849C>A		intron_variant		1		A2
LTBP4	ENST00000599016.5	c.17-1849C>A		intron_variant, NMD_transcript_variant		3
LTBP4	ENST00000600026.5	c.17-1849C>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152164 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000299 AC: 36 AN: 120602 Hom.: 1 AF XY: 0.000271 AC XY: 18 AN XY: 66388

Gnomad AFR exome AF: 0.00624

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000275

GnomAD4 exome AF: 0.000215 AC: 295 AN: 1371404 Hom.: 2 Cov.: 33 AF XY: 0.000183 AC XY: 124 AN XY: 676764

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.000545

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000296

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000466

Gnomad4 OTH exome AF: 0.000558

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152282 Hom.: 3 Cov.: 30 AF XY: 0.00223 AC XY: 166 AN XY: 74470

Gnomad4 AFR AF: 0.00804

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LTBP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	12
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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

LitVar

Other links and lift over

dbSNP: rs187391485; hg19: chr19-41103254;