rs141810975

Variant names:

• chr19-40611980-C-T
• rs141810975
• NM_001042545.2:c.2175C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40611980-C-T
• chr19-40611980-C-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042545.2(LTBP4):​c.2175C>T​(p.Cys725Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,611,810 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.480
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-40611980-C-T is Benign according to our data. Variant chr19-40611980-C-T is described in ClinVar as Benign. ClinVar VariationId is 226720.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 = 0.00886 (1348/152182) while in subpopulation AFR AF = 0.0315 (1306/41510). AF 95% confidence interval is 0.03. There are 19 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.2175C>T	p.Cys725Cys	synonymous	Exon 14 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.2376C>T	p.Cys792Cys	synonymous	Exon 17 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.2265C>T	p.Cys755Cys	synonymous	Exon 17 of 33	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.2175C>T	p.Cys725Cys	synonymous	Exon 14 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.2376C>T	p.Cys792Cys	synonymous	Exon 17 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.2265C>T	p.Cys755Cys	synonymous	Exon 17 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1347 AN: 152064 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00192 AC: 473 AN: 245904 AF XY: 0.00148

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000826 AC: 1205 AN: 1459628 Hom.: 13 Cov.: 56 AF XY: 0.000708 AC XY: 514 AN XY: 725968

African (AFR) AF: 0.0310 AC: 1037 AN: 33408

American (AMR) AF: 0.000854 AC: 38 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39602

South Asian (SAS) AF: 0.0000815 AC: 7 AN: 85882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1110904

Other (OTH) AF: 0.00164 AC: 99 AN: 60274

GnomAD4 genome AF: 0.00886 AC: 1348 AN: 152182 Hom.: 19 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74396

African (AFR) AF: 0.0315 AC: 1306 AN: 41510

American (AMR) AF: 0.00170 AC: 26 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67994

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00486 Hom.: 6

Bravo AF: 0.00991

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)
-	-	1	LTBP4-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		0.48
PromoterAI		0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: -2

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

Other links and lift over

dbSNP: rs141810975; hg19: chr19-41117886;