rs80192963

Positions:

• chr19-40627363-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000396819.8(LTBP4):​c.4366+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,490,270 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (50 hom.)
• Consequence: LTBP4 ENST00000396819.8 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.623

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-40627363-C-T is Benign according to our data. Variant chr19-40627363-C-T is described in ClinVar as [Benign]. Clinvar id is 226723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40627363-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.4366+8C>T		splice_region_variant, intron_variant		ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.4567+8C>T		splice_region_variant, intron_variant			NP_001036009.1
LTBP4	NM_003573.2	c.4456+8C>T		splice_region_variant, intron_variant			NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.4366+8C>T		splice_region_variant, intron_variant		1	NM_001042545.2	ENSP00000380031	P3

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2591 AN: 152118 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00925

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00662 AC: 811 AN: 122562 Hom.: 12 AF XY: 0.00557 AC XY: 361 AN XY: 64754

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000300

Gnomad FIN exome AF: 0.00727

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.00367 AC: 4907 AN: 1338034 Hom.: 50 Cov.: 32 AF XY: 0.00346 AC XY: 2263 AN XY: 653592

Gnomad4 AFR exome AF: 0.0570

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000411

Gnomad4 FIN exome AF: 0.00771

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.0170 AC: 2593 AN: 152236 Hom.: 54 Cov.: 32 AF XY: 0.0171 AC XY: 1271 AN XY: 74414

Gnomad4 AFR AF: 0.0513

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00925

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0111 Hom.: 12

Bravo AF: 0.0187

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	4567+8C>T in intron 31 of LTBP4: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 4.5% (189/4172) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs80192963). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2016	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.28

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: rs80192963; hg19: chr19-41133268;