19-40593167-T-C

Position:

• chr19-40593167-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000204005.13(LTBP4):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTBP4 ENST00000204005.13 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.19

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_003573.2	c.2T>C	p.Met1?	start_lost	1/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000204005.13	c.2T>C	p.Met1?	start_lost	1/33	1		ENSP00000204005	A2
LTBP4	ENST00000600026.5	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/5	3		ENSP00000483230

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2018

A c.2 T>C variant of uncertain significance in the LTBP4 gene has not been published as pathogenic or been reported as benign to our knowledge, this variant alters the initiator Methionine codon. The resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Of note, there are multiple transcripts of the LTBP4 gene with at least three alternative first exons, each with a different translational start site. It is not known whether loss of the Met1 translational start site in this transcript is sufficient to affect protein function, and, in the absence of functional studies, the physiological consequence of this variant cannot be precisely determined. Finally, the c.2 T>C variant is not observed in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear if this variant is pathogenic or rare benign." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.10
DANN	Benign	0.53
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	0.48	N
REVEL	Benign	0.21
Sift	Uncertain	0.021	D
Vest4		0.062
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0458);
MVP		0.46
ClinPred		0.18	T
GERP RS		-6.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1250364777; hg19: chr19-41099073;