rs73544980

Variant names:

• chr19-40612201-A-G
• rs73544980
• NM_001042545.2:c.2299+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042544.1(LTBP4):​c.2500+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00091 in 1,590,814 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: LTBP4 NM_001042544.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.08
• 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: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-40612201-A-G is Benign according to our data. Variant chr19-40612201-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00435 (662/152272) while in subpopulation AFR AF = 0.015 (623/41544). AF 95% confidence interval is 0.014. There are 6 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.2299+9A>G		intron	N/A	NP_001036010.1
	LTBP4	NM_001042544.1		c.2500+9A>G		intron	N/A	NP_001036009.1
	LTBP4	NM_003573.2		c.2389+9A>G		intron	N/A	NP_003564.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.2299+9A>G		intron	N/A	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.2500+9A>G		intron	N/A	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.2389+9A>G		intron	N/A	ENSP00000204005.10

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000989 AC: 212 AN: 214278 AF XY: 0.000828

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000679

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000567

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000922

GnomAD4 exome AF: 0.000546 AC: 786 AN: 1438542 Hom.: 4 Cov.: 33 AF XY: 0.000509 AC XY: 363 AN XY: 713354

African (AFR) AF: 0.0173 AC: 571 AN: 33078

American (AMR) AF: 0.000810 AC: 34 AN: 41952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 38836

South Asian (SAS) AF: 0.0000480 AC: 4 AN: 83266

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49466

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5678

European-Non Finnish (NFE) AF: 0.0000763 AC: 84 AN: 1101078

Other (OTH) AF: 0.00143 AC: 85 AN: 59516

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74442

African (AFR) AF: 0.0150 AC: 623 AN: 41544

American (AMR) AF: 0.00183 AC: 28 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00487

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		-1.1
PromoterAI		-0.018	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: rs73544980; hg19: chr19-41118107;