chr19-40597228-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003573.2(LTBP4):​c.17-1969C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,481,034 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: LTBP4 NM_003573.2 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-40597228-C-A is Benign according to our data. Variant chr19-40597228-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3349609.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000467 (621/1328834) while in subpopulation NFE AF = 0.000577 (608/1054094). AF 95% confidence interval is 0.000539. There are 1 homozygotes in GnomAdExome4. There are 288 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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>A		intron	N/A	NP_003564.2	B3KXY6
	LTBP4	NM_001042544.1		c.-7C>A		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>A		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1969C>A		intron	N/A	ENSP00000482179.1	A0A087WYX7
	LTBP4	ENST00000600026.5	TSL:3	n.17-1969C>A		intron	N/A	ENSP00000483230.1	A0A087X0A7

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152092 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

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: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000117 AC: 10 AN: 85316 AF XY: 0.0000828

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: 0.000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000467 AC: 621 AN: 1328834 Hom.: 1 Cov.: 32 AF XY: 0.000440 AC XY: 288 AN XY: 654078

African (AFR) AF: 0.0000374 AC: 1 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: 0.00 AC: 0 AN: 72860

European-Finnish (FIN) AF: 0.0000600 AC: 2 AN: 33308

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

European-Non Finnish (NFE) AF: 0.000577 AC: 608 AN: 1054094

Other (OTH) AF: 0.000181 AC: 10 AN: 55214

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.000188 AC XY: 14 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000136

ClinVar

ClinVar submissions as Germline

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	-0.57
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-0.55
PromoterAI		0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

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;