19-40601522-C-T

Variant names:

• chr19-40601522-C-T
• rs185400394
• NM_001042545.2:c.135C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000396819.8(LTBP4):​c.135C>T​(p.Cys45Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,493,690 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (52 hom.)
• Consequence: LTBP4 ENST00000396819.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.653
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-40601522-C-T is Benign according to our data. Variant chr19-40601522-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.653 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00626 (952/152138) while in subpopulation NFE AF = 0.00954 (648/67952). AF 95% confidence interval is 0.00893. There are 6 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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: ENST00000396819.8. 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.135C>T	p.Cys45Cys	synonymous	Exon 1 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.451+1345C>T		intron	N/A	NP_001036009.1
	LTBP4	NM_003573.2		c.340+1345C>T		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.135C>T	p.Cys45Cys	synonymous	Exon 1 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.451+1345C>T		intron	N/A	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.340+1345C>T		intron	N/A	ENSP00000204005.10

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 954 AN: 152030 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00547 AC: 525 AN: 95970 AF XY: 0.00527

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.00915

Gnomad OTH exome AF: 0.00630

GnomAD4 exome AF: 0.00685 AC: 9183 AN: 1341552 Hom.: 52 Cov.: 31 AF XY: 0.00691 AC XY: 4571 AN XY: 661842

African (AFR) AF: 0.000956 AC: 26 AN: 27202

American (AMR) AF: 0.00349 AC: 107 AN: 30666

Ashkenazi Jewish (ASJ) AF: 0.0000842 AC: 2 AN: 23762

East Asian (EAS) AF: 0.00 AC: 0 AN: 30468

South Asian (SAS) AF: 0.00115 AC: 86 AN: 74682

European-Finnish (FIN) AF: 0.0179 AC: 602 AN: 33682

Middle Eastern (MID) AF: 0.00109 AC: 5 AN: 4574

European-Non Finnish (NFE) AF: 0.00763 AC: 8093 AN: 1060648

Other (OTH) AF: 0.00469 AC: 262 AN: 55868

GnomAD4 genome AF: 0.00626 AC: 952 AN: 152138 Hom.: 6 Cov.: 31 AF XY: 0.00640 AC XY: 476 AN XY: 74388

African (AFR) AF: 0.000915 AC: 38 AN: 41552

American (AMR) AF: 0.00477 AC: 73 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00954 AC: 648 AN: 67952

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00806 Hom.: 6

Bravo AF: 0.00487

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	LTBP4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		0.65
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs185400394; hg19: chr19-41107428;