19-40597228-C-G

Variant names:

• chr19-40597228-C-G
• rs761251807
• ENST00000204005.13:c.17-1969C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003573.2(LTBP4):​c.17-1969C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,480,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: LTBP4 NM_003573.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.548
• 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003573.2. 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_003573.2		c.17-1969C>G		intron	N/A	NP_003564.2	B3KXY6
	LTBP4	NM_001042544.1		c.-7C>G		upstream_gene	N/A	NP_001036009.1	Q8N2S1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000204005.13	TSL:1	c.17-1969C>G		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1969C>G		intron	N/A	ENSP00000482179.1	A0A087WYX7
	LTBP4	ENST00000600026.5	TSL:3	n.17-1969C>G		intron	N/A	ENSP00000483230.1	A0A087X0A7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1328836 Hom.: 0 Cov.: 32 AF XY: 0.00000459 AC XY: 3 AN XY: 654080

African (AFR) AF: 0.00 AC: 0 AN: 26730

American (AMR) AF: 0.00 AC: 0 AN: 29422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22934

East Asian (EAS) AF: 0.00 AC: 0 AN: 30358

South Asian (SAS) AF: 0.0000274 AC: 2 AN: 72860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3914

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054096

Other (OTH) AF: 0.0000181 AC: 1 AN: 55214

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		-0.55
PromoterAI		0.075	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761251807; hg19: chr19-41103134;