rs34093919

Variant names:

• chr19-40611394-G-A
• rs34093919
• NM_001042545.2:c.2053G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042545.2(LTBP4):​c.2053G>A​(p.Asp685Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0101 in 1,603,676 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D685G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.010 (119 hom.)
• Consequence: LTBP4 NM_001042545.2 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.62
• Publications: 18 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-40611394-G-A is Benign according to our data. Variant chr19-40611394-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00732 (1115/152356) while in subpopulation NFE AF = 0.0109 (744/68034). AF 95% confidence interval is 0.0103. There are 11 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. 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.2053G>A	p.Asp685Asn	missense splice_region	Exon 13 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.2254G>A	p.Asp752Asn	missense splice_region	Exon 16 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.2143G>A	p.Asp715Asn	missense splice_region	Exon 16 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.2053G>A	p.Asp685Asn	missense splice_region	Exon 13 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.2254G>A	p.Asp752Asn	missense splice_region	Exon 16 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.2143G>A	p.Asp715Asn	missense splice_region	Exon 16 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1115 AN: 152238 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00769 AC: 1838 AN: 239032 AF XY: 0.00781

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000409

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.0103 AC: 15013 AN: 1451320 Hom.: 119 Cov.: 32 AF XY: 0.0101 AC XY: 7322 AN XY: 721674

African (AFR) AF: 0.000932 AC: 31 AN: 33268

American (AMR) AF: 0.00114 AC: 51 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00204 AC: 175 AN: 85946

European-Finnish (FIN) AF: 0.0208 AC: 1009 AN: 48528

Middle Eastern (MID) AF: 0.000239 AC: 1 AN: 4180

European-Non Finnish (NFE) AF: 0.0120 AC: 13345 AN: 1109212

Other (OTH) AF: 0.00660 AC: 396 AN: 60016

GnomAD4 genome AF: 0.00732 AC: 1115 AN: 152356 Hom.: 11 Cov.: 32 AF XY: 0.00801 AC XY: 597 AN XY: 74512

African (AFR) AF: 0.00180 AC: 75 AN: 41588

American (AMR) AF: 0.00124 AC: 19 AN: 15310

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0250 AC: 266 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0109 AC: 744 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00997 Hom.: 34

Bravo AF: 0.00560

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00264 AC: 10

ESP6500EA AF: 0.00782 AC: 64

ExAC AF: 0.00813 AC: 980

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.00824

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0092	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.62
Sift	Benign	0.054	T
Sift4G	Uncertain	0.038	D
Polyphen		0.50	P
Vest4		0.56
MVP		0.76
MPC		0.95
ClinPred		0.035	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.84
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34093919; hg19: chr19-41117300;