rs80192963

Variant names:

• chr19-40627363-C-T
• rs80192963
• NM_001042545.2:c.4366+8C>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.4366+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,490,270 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (50 hom.)
• Consequence: LTBP4 NM_001042545.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.623
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-40627363-C-T is Benign according to our data. Variant chr19-40627363-C-T is described in ClinVar as Benign. ClinVar VariationId is 226723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. 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_001042545.2	MANE Select	c.4366+8C>T		splice_region intron	N/A	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.4567+8C>T		splice_region intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.4456+8C>T		splice_region intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.4366+8C>T		splice_region intron	N/A	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.4567+8C>T		splice_region intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.4456+8C>T		splice_region intron	N/A	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2591 AN: 152118 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00925

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00662 AC: 811 AN: 122562 AF XY: 0.00557

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00727

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.00367 AC: 4907 AN: 1338034 Hom.: 50 Cov.: 32 AF XY: 0.00346 AC XY: 2263 AN XY: 653592

African (AFR) AF: 0.0570 AC: 1742 AN: 30548

American (AMR) AF: 0.00411 AC: 124 AN: 30178

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 288 AN: 21084

East Asian (EAS) AF: 0.00 AC: 0 AN: 36700

South Asian (SAS) AF: 0.000411 AC: 29 AN: 70510

European-Finnish (FIN) AF: 0.00771 AC: 254 AN: 32934

Middle Eastern (MID) AF: 0.0100 AC: 50 AN: 4986

European-Non Finnish (NFE) AF: 0.00195 AC: 2056 AN: 1055250

Other (OTH) AF: 0.00652 AC: 364 AN: 55844

GnomAD4 genome AF: 0.0170 AC: 2593 AN: 152236 Hom.: 54 Cov.: 32 AF XY: 0.0171 AC XY: 1271 AN XY: 74414

African (AFR) AF: 0.0513 AC: 2133 AN: 41546

American (AMR) AF: 0.00850 AC: 130 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00925 AC: 98 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00218 AC: 148 AN: 68014

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0120 Hom.: 12

Bravo AF: 0.0187

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.28
PhyloP100		0.62
PromoterAI		0.0094	Neutral
Mutation Taster		=100/0	polymorphism

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: rs80192963; hg19: chr19-41133268;