19-40592965-C-T

Position:

• chr19-40592965-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000600026.5(LTBP4):​c.-201C>T variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 591,688 control chromosomes in the GnomAD database, including 2,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (571 hom., cov: 32)
  • Exomes 𝑓: 0.082 (1810 hom.)
• Consequence: LTBP4 ENST00000600026.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.785

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-40592965-C-T is Benign according to our data. Variant chr19-40592965-C-T is described in ClinVar as [Benign]. Clinvar id is 678508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000600026.5	c.-201C>T		5_prime_UTR_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12825 AN: 151892 Hom.: 566 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0805

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.0749

GnomAD4 exome AF: 0.0825 AC: 36263 AN: 439678 Hom.: 1810 Cov.: 5 AF XY: 0.0853 AC XY: 19859 AN XY: 232900

Gnomad4 AFR exome AF: 0.0975

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.00830

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0838

Gnomad4 NFE exome AF: 0.0843

Gnomad4 OTH exome AF: 0.0831

GnomAD4 genome AF: 0.0845 AC: 12843 AN: 152010 Hom.: 571 Cov.: 32 AF XY: 0.0841 AC XY: 6250 AN XY: 74300

Gnomad4 AFR AF: 0.0986

Gnomad4 AMR AF: 0.0581

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.0805

Gnomad4 NFE AF: 0.0840

Gnomad4 OTH AF: 0.0798

Alfa AF: 0.0833 Hom.: 60

Bravo AF: 0.0815

Asia WGS AF: 0.108 AC: 374 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56013937; hg19: chr19-41098871;