rs553283319

Positions:

• chr19-40600141-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000308370.11(LTBP4):​c.415A>G​(p.Arg139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,103,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LTBP4 ENST00000308370.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11950484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042544.1	c.415A>G	p.Arg139Gly	missense_variant	4/33		NP_001036009.1
LTBP4	NM_003573.2	c.304A>G	p.Arg102Gly	missense_variant	4/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000308370.11	c.415A>G	p.Arg139Gly	missense_variant	4/33	1		ENSP00000311905	A2
LTBP4	ENST00000204005.13	c.304A>G	p.Arg102Gly	missense_variant	4/33	1		ENSP00000204005	A2
LTBP4	ENST00000593738.1	n.158A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000208 AC: 23 AN: 1103782 Hom.: 0 Cov.: 31 AF XY: 0.0000210 AC XY: 11 AN XY: 522588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

The p.Arg139Gly variant in LTBP4 has not been previously reported in individuals with pulmonary disease. Data from large population studies is insufficient to a ssess the frequency of this variant. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, the clinical significance of the p.Arg139Gly variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.25
Sift	Benign	0.20	T;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.0020	.;B
Vest4		0.37
MVP		0.62
MPC		1.0
ClinPred		0.40	T
GERP RS		3.5
Varity_R		0.23
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs553283319; hg19: chr19-41106047;