19-40610549-C-T

Variant names:

• chr19-40610549-C-T
• rs33937741
• NM_001042545.2:c.1702C>T

Variant summary

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

The NM_001042545.2(LTBP4):​c.1702C>T​(p.Arg568Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,072 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R568G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.1702C>T	p.Arg568Cys	missense_variant	Exon 12 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.1903C>T	p.Arg635Cys	missense_variant	Exon 15 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.1792C>T	p.Arg598Cys	missense_variant	Exon 15 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.1702C>T	p.Arg568Cys	missense_variant	Exon 12 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000464 AC: 1 AN: 215696 Hom.: 0 AF XY: 0.00000840 AC XY: 1 AN XY: 119106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441072 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 716524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.56
MutPred		0.50		.;Gain of catalytic residue at D631 (P = 0.1882);.;
MVP		0.62
MPC		1.2
ClinPred		0.97	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.38
gMVP		0.68

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: rs33937741; hg19: chr19-41116455;