rs143282840

Variant names:

• chr14-74585866-G-A
• rs143282840
• NM_000428.3:c.818C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-74585866-G-A
• chr14-74585866-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000428.3(LTBP2):​c.818C>T​(p.Ser273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,613,290 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S273W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: LTBP2 NM_000428.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.616
• Publications: 4 publications found

Genes affected

LTBP2 (HGNC:6715): (latent transforming growth factor beta binding protein 2) The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]

LTBP2 Gene-Disease associations (from GenCC):

• glaucoma 3, primary congenital, D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Weill-Marchesani syndrome 3

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma secondary to spherophakia/ectopia lentis and megalocornea

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008027643).
• BP6: Variant 14-74585866-G-A is Benign according to our data. Variant chr14-74585866-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314315.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000428.3. 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
	LTBP2	NM_000428.3	MANE Select	c.818C>T	p.Ser273Leu	missense	Exon 3 of 36	NP_000419.1	Q14767

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.818C>T	p.Ser273Leu	missense	Exon 3 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.818C>T	p.Ser273Leu	missense	Exon 3 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.818C>T	p.Ser273Leu	missense	Exon 3 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000561 AC: 140 AN: 249336 AF XY: 0.000622

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000417 AC: 609 AN: 1461036 Hom.: 4 Cov.: 32 AF XY: 0.000435 AC XY: 316 AN XY: 726832

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.000850 AC: 38 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.000361 AC: 401 AN: 1111280

Other (OTH) AF: 0.000315 AC: 19 AN: 60348

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74440

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67974

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000551 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Glaucoma 3, primary congenital, D (1)
-	1	-	Weill-Marchesani syndrome (1)
-	1	-	Weill-Marchesani syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.20
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.62
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.36
MPC		0.12
ClinPred		0.0097	T
GERP RS		-9.1
Varity_R		0.028
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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: rs143282840; hg19: chr14-75052569; COSMIC: COSV56205840;