NM_001042545.2:c.2565C>G

Variant names:

• chr19-40613923-C-G
• rs2077407
• NM_001042545.2:c.2565C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001042545.2(LTBP4):​c.2565C>G​(p.Asp855Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D855D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.2565C>G	p.Asp855Glu	missense_variant	Exon 18 of 30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2766C>G	p.Asp922Glu	missense_variant	Exon 21 of 33		NP_001036009.1
LTBP4	NM_003573.2	c.2655C>G	p.Asp885Glu	missense_variant	Exon 21 of 33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2565C>G	p.Asp855Glu	missense_variant	Exon 18 of 30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461468 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727014

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.9	.;H;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;D;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.51
MutPred		0.82		.;Gain of phosphorylation at S925 (P = 0.2307);.;.;
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		-1.3
Varity_R		0.069
gMVP		0.85

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: rs2077407; hg19: chr19-41119829;