19-40597416-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000308370.11(LTBP4):c.146+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,478,074 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (5 hom.)
• Consequence: LTBP4 ENST00000308370.11 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45

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 19-40597416-A-G is Benign according to our data. Variant chr19-40597416-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1178562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00341 (519/152126) while in subpopulation AFR AF= 0.0122 (506/41500). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042544.1	c.146+36A>G		intron_variant
LTBP4	NM_003573.2	c.17-1781A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000204005.13	c.17-1781A>G		intron_variant		1		A2
LTBP4	ENST00000308370.11	c.146+36A>G		intron_variant		1		A2
LTBP4	ENST00000599016.5	c.17-1781A>G		intron_variant, NMD_transcript_variant		3
LTBP4	ENST00000600026.5	c.17-1781A>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 518 AN: 152014 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000373 AC: 34 AN: 91162 Hom.: 0 AF XY: 0.000214 AC XY: 11 AN XY: 51384

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000296

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: 0.0000279

Gnomad OTH exome AF: 0.000377

GnomAD4 exome AF: 0.000284 AC: 377 AN: 1325948 Hom.: 5 Cov.: 33 AF XY: 0.000250 AC XY: 163 AN XY: 651570

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000347

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000271

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000115

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152126 Hom.: 5 Cov.: 30 AF XY: 0.00360 AC XY: 268 AN XY: 74382

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00449

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.2
Dann	Benign	0.41

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: rs79235206; hg19: chr19-41103322;