rs2290427

Positions:

• chr2-33280072-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_206943.4(LTBP1):​c.3026C>A​(p.Pro1009Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0203 in 1,613,984 control chromosomes in the GnomAD database, including 407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (21 hom., cov: 32)
  • Exomes 𝑓: 0.021 (386 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43

Genes affected

LTBP1 (HGNC:6714): (latent transforming growth factor beta binding protein 1) The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008792281).
• BP6: Variant 2-33280072-C-A is Benign according to our data. Variant chr2-33280072-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0145 (2212/152240) while in subpopulation EAS AF= 0.0253 (131/5186). AF 95% confidence interval is 0.0217. There are 21 homozygotes in gnomad4. There are 1018 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP1	NM_206943.4	c.3026C>A	p.Pro1009Gln	missense_variant	19/34	ENST00000404816.7	NP_996826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP1	ENST00000404816.7	c.3026C>A	p.Pro1009Gln	missense_variant	19/34	5	NM_206943.4	ENSP00000386043	P3
	ENST00000650179.1	n.227+853G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2213 AN: 152122 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0154 AC: 3877 AN: 251246 Hom.: 49 AF XY: 0.0154 AC XY: 2090 AN XY: 135768

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0237

Gnomad SAS exome AF: 0.00553

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0209 AC: 30613 AN: 1461744 Hom.: 386 Cov.: 31 AF XY: 0.0203 AC XY: 14750 AN XY: 727168

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.00865

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.0400

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0145 AC: 2212 AN: 152240 Hom.: 21 Cov.: 32 AF XY: 0.0137 AC XY: 1018 AN XY: 74450

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0191 Hom.: 73

Bravo AF: 0.0137

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0209 AC: 180

ExAC AF: 0.0152 AC: 1850

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T;T;T
MetaRNN	Benign	0.0088	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.67
MPC		0.57
ClinPred		0.031	T
GERP RS		5.5
Varity_R		0.54
gMVP		0.77

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: rs2290427; hg19: chr2-33505139; COSMIC: COSV63199955;