rs41470347

Variant names:

• chr19-40611848-C-A
• rs41470347
• NM_001042545.2:c.2054-11C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-40611848-C-A
• chr19-40611848-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):​c.2054-11C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,604,842 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (367 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5316 hom.)
• Consequence: LTBP4 NM_001042545.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.306
• Publications: 3 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: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-40611848-C-A is Benign according to our data. Variant chr19-40611848-C-A is described in ClinVar as Benign. ClinVar VariationId is 226719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.2054-11C>A		intron_variant	Intron 13 of 29	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.2255-11C>A		intron_variant	Intron 16 of 32		NP_001036009.1
LTBP4	NM_003573.2	c.2144-11C>A		intron_variant	Intron 16 of 32		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.2054-11C>A		intron_variant	Intron 13 of 29	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8392 AN: 152024 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0596 AC: 14004 AN: 234946 AF XY: 0.0624

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0396

Gnomad ASJ exome AF: 0.0963

Gnomad EAS exome AF: 0.000231

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0874

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.0808 AC: 117335 AN: 1452702 Hom.: 5316 Cov.: 32 AF XY: 0.0803 AC XY: 57908 AN XY: 721446

African (AFR) AF: 0.0127 AC: 424 AN: 33282

American (AMR) AF: 0.0414 AC: 1813 AN: 43782

Ashkenazi Jewish (ASJ) AF: 0.0969 AC: 2508 AN: 25884

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39306

South Asian (SAS) AF: 0.0448 AC: 3782 AN: 84388

European-Finnish (FIN) AF: 0.0295 AC: 1560 AN: 52840

Middle Eastern (MID) AF: 0.119 AC: 684 AN: 5754

European-Non Finnish (NFE) AF: 0.0921 AC: 101955 AN: 1107476

Other (OTH) AF: 0.0767 AC: 4604 AN: 59990

GnomAD4 genome AF: 0.0551 AC: 8385 AN: 152140 Hom.: 367 Cov.: 32 AF XY: 0.0513 AC XY: 3813 AN XY: 74366

African (AFR) AF: 0.0159 AC: 660 AN: 41530

American (AMR) AF: 0.0532 AC: 813 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3470

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5142

South Asian (SAS) AF: 0.0407 AC: 196 AN: 4820

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10610

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0872 AC: 5929 AN: 67974

Other (OTH) AF: 0.0635 AC: 133 AN: 2096

Alfa AF: 0.0744 Hom.: 273

Bravo AF: 0.0565

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

2255-11C>A in intron 16 of LTBP4: This variant is not expected to have clinical significance because it has been identified in 8.2% (683/8378) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs41470347). -

Oct 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		-0.31
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs41470347; hg19: chr19-41117754;