rs55659002

Positions:

• chr19-41342037-TG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000221930.6(TGFB1):​c.713-8del variant causes a splice region, splice polypyrimidine tract, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 ENST00000221930.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.563

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 197687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41342037-TG-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.713-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.713-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.713-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000660.7	ENSP00000221930	P1

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

GnomAD3 exomes AF: 0.0128 AC: 3207 AN: 251012 Hom.: 32 AF XY: 0.0132 AC XY: 1788 AN XY: 135764

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 SAS exome AF: 0.00650

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

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00674

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0134

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

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0152

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 18, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs55659002; hg19: chr19-41847942;