19-40597233-C-G

Variant names:

• chr19-40597233-C-G
• rs772816721
• ENST00000204005.13:c.17-1964C>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.17-1964C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,336,510 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: LTBP4 NM_003573.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

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.17-1964C>G		intron	N/A	NP_003564.2	B3KXY6
	LTBP4	NM_001042544.1		c.-2C>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.17-1964C>G		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1964C>G		intron	N/A	ENSP00000482179.1	A0A087WYX7
	LTBP4	ENST00000600026.5	TSL:3	n.17-1964C>G		intron	N/A	ENSP00000483230.1	A0A087X0A7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000110 AC: 1 AN: 90852 AF XY: 0.0000195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000527

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1336510 Hom.: 0 Cov.: 33 AF XY: 0.00000456 AC XY: 3 AN XY: 658308

African (AFR) AF: 0.00 AC: 0 AN: 26978

American (AMR) AF: 0.0000326 AC: 1 AN: 30632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23330

East Asian (EAS) AF: 0.00 AC: 0 AN: 30750

South Asian (SAS) AF: 0.00 AC: 0 AN: 74056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3966

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1057742

Other (OTH) AF: 0.0000180 AC: 1 AN: 55518

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.64
PhyloP100		-0.0090
PromoterAI		0.033	Neutral

Splicing

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

Other links and lift over

dbSNP: rs772816721; hg19: chr19-41103139;