19-40597348-C-A

Variant names:

• chr19-40597348-C-A
• rs187391485
• ENST00000308370.11:c.114C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001042544.1(LTBP4):​c.114C>A​(p.Val38Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,523,686 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: LTBP4 NM_001042544.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.670
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-40597348-C-A is Benign according to our data. Variant chr19-40597348-C-A is described in ClinVar as Benign. ClinVar VariationId is 3035573.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00232 (353/152282) while in subpopulation AFR AF = 0.00804 (334/41556). AF 95% confidence interval is 0.00733. There are 3 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 30. 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_001042544.1		c.114C>A	p.Val38Val	synonymous	Exon 1 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.17-1849C>A		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000308370.11	TSL:1	c.114C>A	p.Val38Val	synonymous	Exon 1 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.17-1849C>A		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1849C>A		intron	N/A	ENSP00000482179.1	A0A087WYX7

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152164 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000299 AC: 36 AN: 120602 AF XY: 0.000271

Gnomad AFR exome AF: 0.00624

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000275

GnomAD4 exome AF: 0.000215 AC: 295 AN: 1371404 Hom.: 2 Cov.: 33 AF XY: 0.000183 AC XY: 124 AN XY: 676764

African (AFR) AF: 0.00798 AC: 236 AN: 29584

American (AMR) AF: 0.000545 AC: 19 AN: 34868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24696

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33820

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34670

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5640

European-Non Finnish (NFE) AF: 0.00000466 AC: 5 AN: 1073010

Other (OTH) AF: 0.000558 AC: 32 AN: 57320

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152282 Hom.: 3 Cov.: 30 AF XY: 0.00223 AC XY: 166 AN XY: 74470

African (AFR) AF: 0.00804 AC: 334 AN: 41556

American (AMR) AF: 0.000915 AC: 14 AN: 15298

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: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

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

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LTBP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.56
PhyloP100		0.67
PromoterAI		-0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
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: rs187391485; hg19: chr19-41103254;