rs7367

Variant names:

• chr19-40623937-C-T
• rs7367
• NM_001042545.2:c.3687C>T

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.3687C>T​(p.Asp1229Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,613,160 control chromosomes in the GnomAD database, including 144,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20872 hom., cov: 32)
  • Exomes 𝑓: 0.40 (123676 hom.)
• Consequence: LTBP4 NM_001042545.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.517
• Publications: 24 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=-0.65).
• BP6: Variant 19-40623937-C-T is Benign according to our data. Variant chr19-40623937-C-T is described in ClinVar as Benign. ClinVar VariationId is 163950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.517 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 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.3687C>T	p.Asp1229Asp	splice_region synonymous	Exon 26 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.3888C>T	p.Asp1296Asp	splice_region synonymous	Exon 29 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.3777C>T	p.Asp1259Asp	splice_region synonymous	Exon 29 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.3687C>T	p.Asp1229Asp	splice_region synonymous	Exon 26 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.3888C>T	p.Asp1296Asp	splice_region synonymous	Exon 29 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.3777C>T	p.Asp1259Asp	splice_region synonymous	Exon 29 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75512 AN: 152018 Hom.: 20830 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.430 AC: 106381 AN: 247670 AF XY: 0.433

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.404 AC: 590242 AN: 1461024 Hom.: 123676 Cov.: 49 AF XY: 0.408 AC XY: 296745 AN XY: 726732

African (AFR) AF: 0.763 AC: 25548 AN: 33472

American (AMR) AF: 0.306 AC: 13646 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14344 AN: 26106

East Asian (EAS) AF: 0.322 AC: 12777 AN: 39688

South Asian (SAS) AF: 0.521 AC: 44940 AN: 86214

European-Finnish (FIN) AF: 0.485 AC: 25857 AN: 53362

Middle Eastern (MID) AF: 0.466 AC: 2687 AN: 5764

European-Non Finnish (NFE) AF: 0.381 AC: 423986 AN: 1111436

Other (OTH) AF: 0.439 AC: 26457 AN: 60318

GnomAD4 genome AF: 0.497 AC: 75612 AN: 152136 Hom.: 20872 Cov.: 32 AF XY: 0.499 AC XY: 37159 AN XY: 74394

African (AFR) AF: 0.742 AC: 30795 AN: 41502

American (AMR) AF: 0.366 AC: 5598 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1929 AN: 3472

East Asian (EAS) AF: 0.352 AC: 1816 AN: 5162

South Asian (SAS) AF: 0.523 AC: 2523 AN: 4828

European-Finnish (FIN) AF: 0.503 AC: 5326 AN: 10580

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26262 AN: 67978

Other (OTH) AF: 0.456 AC: 964 AN: 2112

Alfa AF: 0.422 Hom.: 32363

Bravo AF: 0.494

Asia WGS AF: 0.458 AC: 1590 AN: 3478

EpiCase AF: 0.399

EpiControl AF: 0.394

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=71/29	polymorphism (auto)

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: rs7367; hg19: chr19-41129842; COSMIC: COSV108020536; COSMIC: COSV108020536;