chr2-33280072-C-A

Variant names:

• chr2-33280072-C-A
• rs2290427
• NM_206943.4:c.3026C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 19 publications found

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]

LTBP1 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 2E

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000285577 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008792281).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206943.4. 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
	LTBP1	NM_206943.4	MANE Select	c.3026C>A	p.Pro1009Gln	missense	Exon 19 of 34	NP_996826.3
	LTBP1	NM_001394905.1		c.2867C>A	p.Pro956Gln	missense	Exon 19 of 34	NP_001381834.1
	LTBP1	NM_000627.4		c.2048C>A	p.Pro683Gln	missense	Exon 15 of 30	NP_000618.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	ENST00000404816.7	TSL:5 MANE Select	c.3026C>A	p.Pro1009Gln	missense	Exon 19 of 34	ENSP00000386043.2
	LTBP1	ENST00000407925.5	TSL:1	c.2048C>A	p.Pro683Gln	missense	Exon 15 of 30	ENSP00000384091.1
	LTBP1	ENST00000418533.6	TSL:1	c.2048C>A	p.Pro683Gln	missense	Exon 15 of 29	ENSP00000393057.2

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

GnomAD2 exomes AF: 0.0154 AC: 3877 AN: 251246 AF XY: 0.0154

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 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

African (AFR) AF: 0.00388 AC: 130 AN: 33476

American (AMR) AF: 0.00865 AC: 387 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 517 AN: 26136

East Asian (EAS) AF: 0.0400 AC: 1589 AN: 39694

South Asian (SAS) AF: 0.00605 AC: 522 AN: 86234

European-Finnish (FIN) AF: 0.0132 AC: 707 AN: 53416

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0230 AC: 25623 AN: 1111910

Other (OTH) AF: 0.0183 AC: 1108 AN: 60394

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

African (AFR) AF: 0.00402 AC: 167 AN: 41544

American (AMR) AF: 0.0147 AC: 225 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0253 AC: 131 AN: 5186

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0205 AC: 1396 AN: 68016

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0186 Hom.: 141

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 v4.9

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
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.67
MPC		0.57
ClinPred		0.031	T
GERP RS		5.5
Varity_R		0.54
gMVP		0.77
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

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