rs2077407

Variant names:

• chr19-40613923-C-T
• rs2077407
• NM_001042545.2:c.2565C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40613923-C-T
• chr19-40613923-C-A
• chr19-40613923-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001042545.2(LTBP4):​c.2565C>T​(p.Asp855Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,613,452 control chromosomes in the GnomAD database, including 6,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (497 hom., cov: 31)
  • Exomes 𝑓: 0.086 (5910 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.331
• Publications: 16 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 19-40613923-C-T is Benign according to our data. Variant chr19-40613923-C-T is described in ClinVar as Benign. ClinVar VariationId is 163947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.331 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 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.2565C>T	p.Asp855Asp	synonymous	Exon 18 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.2766C>T	p.Asp922Asp	synonymous	Exon 21 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.2655C>T	p.Asp885Asp	synonymous	Exon 21 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.2565C>T	p.Asp855Asp	synonymous	Exon 18 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.2766C>T	p.Asp922Asp	synonymous	Exon 21 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.2655C>T	p.Asp885Asp	synonymous	Exon 21 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.0738 AC: 11206 AN: 151930 Hom.: 497 Cov.: 31

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0560

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00310

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0776

GnomAD2 exomes AF: 0.0784 AC: 19455 AN: 248080 AF XY: 0.0803

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.0460

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00201

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0929

GnomAD4 exome AF: 0.0865 AC: 126351 AN: 1461404 Hom.: 5910 Cov.: 34 AF XY: 0.0867 AC XY: 63020 AN XY: 726980

African (AFR) AF: 0.0242 AC: 810 AN: 33476

American (AMR) AF: 0.0492 AC: 2199 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3399 AN: 26122

East Asian (EAS) AF: 0.00144 AC: 57 AN: 39698

South Asian (SAS) AF: 0.0598 AC: 5158 AN: 86246

European-Finnish (FIN) AF: 0.114 AC: 6086 AN: 53264

Middle Eastern (MID) AF: 0.120 AC: 692 AN: 5768

European-Non Finnish (NFE) AF: 0.0924 AC: 102770 AN: 1111754

Other (OTH) AF: 0.0858 AC: 5180 AN: 60364

GnomAD4 genome AF: 0.0737 AC: 11204 AN: 152048 Hom.: 497 Cov.: 31 AF XY: 0.0736 AC XY: 5472 AN XY: 74322

African (AFR) AF: 0.0268 AC: 1110 AN: 41492

American (AMR) AF: 0.0559 AC: 854 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 442 AN: 3470

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5156

South Asian (SAS) AF: 0.0519 AC: 250 AN: 4816

European-Finnish (FIN) AF: 0.113 AC: 1192 AN: 10592

Middle Eastern (MID) AF: 0.117 AC: 34 AN: 290

European-Non Finnish (NFE) AF: 0.103 AC: 7004 AN: 67936

Other (OTH) AF: 0.0768 AC: 162 AN: 2110

Alfa AF: 0.0840 Hom.: 511

Bravo AF: 0.0674

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.106

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	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.95
PhyloP100		-0.33
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2077407; hg19: chr19-41119829; COSMIC: COSV52587442; COSMIC: COSV52587442;