rs55659002

Variant names:

• chr19-41342037-TG-T
• rs55659002
• ENST00000597453.1:n.375delC

Variant summary

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

The ENST00000597453.1(TGFB1):​n.375delC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,128 control chromosomes in the GnomAD database, including 213 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 31)
  • Exomes 𝑓: 0.015 (193 hom.)
• Consequence: TGFB1 ENST00000597453.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.563
• Publications: 19 publications found

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 Gene-Disease associations (from GenCC):

• Camurati-Engelmann disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• inflammatory bowel disease, immunodeficiency, and encephalopathy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-41342037-TG-T is Benign according to our data. Variant chr19-41342037-TG-T is described in ClinVar as Benign. ClinVar VariationId is 197687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.011 (1669/152248) while in subpopulation NFE AF = 0.0175 (1189/68010). AF 95% confidence interval is 0.0167. There are 20 homozygotes in GnomAd4. There are 813 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.713-8delC		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.713-5delC		splice_region_variant, intron_variant	Intron 4 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.713-8delC		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_000660.7	ENSP00000221930.4

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1670 AN: 152130 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0128 AC: 3207 AN: 251012 AF XY: 0.0132

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00584

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0149 AC: 21784 AN: 1461880 Hom.: 193 Cov.: 33 AF XY: 0.0148 AC XY: 10763 AN XY: 727238

African (AFR) AF: 0.00239 AC: 80 AN: 33480

American (AMR) AF: 0.00595 AC: 266 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 267 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00674 AC: 581 AN: 86256

European-Finnish (FIN) AF: 0.0148 AC: 790 AN: 53420

Middle Eastern (MID) AF: 0.0499 AC: 288 AN: 5768

European-Non Finnish (NFE) AF: 0.0168 AC: 18696 AN: 1112002

Other (OTH) AF: 0.0134 AC: 812 AN: 60396

GnomAD4 genome AF: 0.0110 AC: 1669 AN: 152248 Hom.: 20 Cov.: 31 AF XY: 0.0109 AC XY: 813 AN XY: 74442

African (AFR) AF: 0.00270 AC: 112 AN: 41546

American (AMR) AF: 0.00766 AC: 117 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10616

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1189 AN: 68010

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.0160 Hom.: 7

Bravo AF: 0.00992

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0180

EpiControl AF: 0.0187

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs55659002; hg19: chr19-41847942; COSMIC: COSV55724566; COSMIC: COSV55724566;