chr19-40597390-C-T

Variant names:

• chr19-40597390-C-T
• rs1461005574
• ENST00000308370.11:c.146+10C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001042544.1(LTBP4):​c.146+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,354,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: LTBP4 NM_001042544.1 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0310
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-40597390-C-T is Benign according to our data. Variant chr19-40597390-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3038923.Status of the report is no_assertion_criteria_provided, 0 stars.

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.146+10C>T		intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.17-1807C>T		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.146+10C>T		intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.17-1807C>T		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1807C>T		intron	N/A	ENSP00000482179.1	A0A087WYX7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000939 AC: 1 AN: 106470 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000242

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1354054 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 667558

African (AFR) AF: 0.00 AC: 0 AN: 28462

American (AMR) AF: 0.00 AC: 0 AN: 32838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24126

East Asian (EAS) AF: 0.00 AC: 0 AN: 32074

South Asian (SAS) AF: 0.00 AC: 0 AN: 76140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.40e-7 AC: 1 AN: 1063920

Other (OTH) AF: 0.00 AC: 0 AN: 56490

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Likely 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	-0.75
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		-0.031
PromoterAI		-0.023	Neutral

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: rs1461005574; hg19: chr19-41103296;