rs553283319

Variant names:

• chr19-40600141-A-G
• rs553283319
• ENST00000308370.11:c.415A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042544.1(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. 13/21 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 NM_001042544.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.397
• Publications: 1 publications found

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]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042544.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042544.1		c.415A>G	p.Arg139Gly	missense	Exon 4 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.304A>G	p.Arg102Gly	missense	Exon 4 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000308370.11	TSL:1	c.415A>G	p.Arg139Gly	missense	Exon 4 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.304A>G	p.Arg102Gly	missense	Exon 4 of 33	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000593738.1	TSL:3	n.158A>G		non_coding_transcript_exon	Exon 1 of 2

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

African (AFR) AF: 0.00 AC: 0 AN: 23088

American (AMR) AF: 0.00 AC: 0 AN: 8590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14482

East Asian (EAS) AF: 0.00 AC: 0 AN: 26630

South Asian (SAS) AF: 0.00 AC: 0 AN: 21754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4204

European-Non Finnish (NFE) AF: 0.0000249 AC: 23 AN: 924150

Other (OTH) AF: 0.00 AC: 0 AN: 44104

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.40
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Uncertain	0.024	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs553283319; hg19: chr19-41106047;