chr19-41332301-G-A

Variant names:

• chr19-41332301-G-A
• rs8179181
• NM_000660.7:c.861-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000660.7(TGFB1):​c.861-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,608,868 control chromosomes in the GnomAD database, including 40,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2707 hom., cov: 31)
  • Exomes 𝑓: 0.22 (37398 hom.)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.512
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-41332301-G-A is Benign according to our data. Variant chr19-41332301-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.861-20C>T		intron_variant	Intron 5 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.864-20C>T		intron_variant	Intron 5 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.861-20C>T		intron_variant	Intron 5 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000600196.2	c.713-20C>T		intron_variant	Intron 4 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.635-20C>T		intron_variant	Intron 3 of 4			ENSP00000504769.1
TGFB1	ENST00000598758.5	n.149-20C>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24647 AN: 152020 Hom.: 2707 Cov.: 31

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.169 AC: 41176 AN: 243806 AF XY: 0.172

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.000552

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.217 AC: 315509 AN: 1456730 Hom.: 37398 Cov.: 33 AF XY: 0.213 AC XY: 154002 AN XY: 724274

African (AFR) AF: 0.0333 AC: 1112 AN: 33392

American (AMR) AF: 0.105 AC: 4646 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5012 AN: 26082

East Asian (EAS) AF: 0.000379 AC: 15 AN: 39594

South Asian (SAS) AF: 0.0758 AC: 6521 AN: 86012

European-Finnish (FIN) AF: 0.232 AC: 12110 AN: 52252

Middle Eastern (MID) AF: 0.124 AC: 663 AN: 5350

European-Non Finnish (NFE) AF: 0.247 AC: 274251 AN: 1109518

Other (OTH) AF: 0.186 AC: 11179 AN: 60138

GnomAD4 genome AF: 0.162 AC: 24647 AN: 152138 Hom.: 2707 Cov.: 31 AF XY: 0.159 AC XY: 11849 AN XY: 74354

African (AFR) AF: 0.0422 AC: 1752 AN: 41532

American (AMR) AF: 0.135 AC: 2060 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 692 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.0661 AC: 319 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2607 AN: 10576

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16687 AN: 67966

Other (OTH) AF: 0.160 AC: 338 AN: 2114

Alfa AF: 0.215 Hom.: 3902

Bravo AF: 0.147

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C0011989:Diaphyseal dysplasia;C4748708:Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1

Aug 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diaphyseal dysplasia Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs8179181; hg19: chr19-41838206;