chr19-40622510-G-A

Variant names:

• chr19-40622510-G-A
• rs35079932
• NM_001042545.2:c.3327G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001042545.2(LTBP4):​c.3327G>A​(p.Val1109Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,613,582 control chromosomes in the GnomAD database, including 2,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2276 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.713
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-40622510-G-A is Benign according to our data. Variant chr19-40622510-G-A is described in ClinVar as Benign. ClinVar VariationId is 226722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.713 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

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.3327G>A	p.Val1109Val	synonymous	Exon 23 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.3528G>A	p.Val1176Val	synonymous	Exon 26 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.3417G>A	p.Val1139Val	synonymous	Exon 26 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.3327G>A	p.Val1109Val	synonymous	Exon 23 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.3528G>A	p.Val1176Val	synonymous	Exon 26 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.3417G>A	p.Val1139Val	synonymous	Exon 26 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5160 AN: 152260 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0390 AC: 9655 AN: 247548 AF XY: 0.0414

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0647

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0520 AC: 76015 AN: 1461204 Hom.: 2276 Cov.: 34 AF XY: 0.0521 AC XY: 37873 AN XY: 726886

African (AFR) AF: 0.00819 AC: 274 AN: 33466

American (AMR) AF: 0.0186 AC: 833 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 1615 AN: 26098

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.0445 AC: 3837 AN: 86232

European-Finnish (FIN) AF: 0.0175 AC: 933 AN: 53300

Middle Eastern (MID) AF: 0.0539 AC: 309 AN: 5730

European-Non Finnish (NFE) AF: 0.0589 AC: 65444 AN: 1111684

Other (OTH) AF: 0.0458 AC: 2765 AN: 60312

GnomAD4 genome AF: 0.0338 AC: 5156 AN: 152378 Hom.: 126 Cov.: 32 AF XY: 0.0319 AC XY: 2377 AN XY: 74512

African (AFR) AF: 0.00969 AC: 403 AN: 41590

American (AMR) AF: 0.0210 AC: 321 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0416 AC: 201 AN: 4830

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10630

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0555 AC: 3774 AN: 68038

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0496 Hom.: 695

Bravo AF: 0.0330

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0574

EpiControl AF: 0.0578

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	LTBP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.7
DANN	Benign	0.69
PhyloP100		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs35079932; hg19: chr19-41128415; COSMIC: COSV52584214; COSMIC: COSV52584214;