rs114749335

Variant names:

• chr19-40608301-G-A
• rs114749335
• NM_001042545.2:c.1238G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-40608301-G-A
• chr19-40608301-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001042544.1(LTBP4):​c.1439G>A​(p.Gly480Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,613,792 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. G480V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: LTBP4 NM_001042544.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.528
• Publications: 0 publications found

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]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008038253).
• BP6: Variant 19-40608301-G-A is Benign according to our data. Variant chr19-40608301-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235240.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00293 (447/152316) while in subpopulation AFR AF = 0.0103 (427/41556). AF 95% confidence interval is 0.00947. There are 3 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042544.1. 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
	LTBP4	NM_001042545.2	MANE Select	c.1238G>A	p.Gly413Asp	missense	Exon 8 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.1439G>A	p.Gly480Asp	missense	Exon 11 of 33	NP_001036009.1
	LTBP4	NM_003573.2		c.1328G>A	p.Gly443Asp	missense	Exon 11 of 33	NP_003564.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.1238G>A	p.Gly413Asp	missense	Exon 8 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.1439G>A	p.Gly480Asp	missense	Exon 11 of 33	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.1328G>A	p.Gly443Asp	missense	Exon 11 of 33	ENSP00000204005.10

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000713 AC: 177 AN: 248238 AF XY: 0.000534

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1461476 Hom.: 1 Cov.: 31 AF XY: 0.000267 AC XY: 194 AN XY: 727034

African (AFR) AF: 0.0109 AC: 366 AN: 33474

American (AMR) AF: 0.000537 AC: 24 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111838

Other (OTH) AF: 0.000663 AC: 40 AN: 60368

GnomAD4 genome AF: 0.00293 AC: 447 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74480

African (AFR) AF: 0.0103 AC: 427 AN: 41556

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.00304

ESP6500AA AF: 0.00974 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000819 AC: 99

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	LTBP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.53
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.14
Sift	Benign	0.82	T
Sift4G	Benign	0.43	T
Polyphen		0.012	B
Vest4		0.31
MVP		0.25
MPC		0.46
ClinPred		0.0058	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.46
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs114749335; hg19: chr19-41114207;