rs104894719

Variant names:

• chr19-41342209-A-G
• rs104894719
• NM_000660.7:c.673T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000660.7(TGFB1):​c.673T>C​(p.Cys225Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.64
• Publications: 16 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000660.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 19-41342209-A-G is Pathogenic according to our data. Variant chr19-41342209-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12528.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000660.7. 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
	TGFB1	NM_000660.7	MANE Select	c.673T>C	p.Cys225Arg	missense	Exon 4 of 7	NP_000651.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	ENST00000221930.6	TSL:1 MANE Select	c.673T>C	p.Cys225Arg	missense	Exon 4 of 7	ENSP00000221930.4
	TGFB1	ENST00000597453.1	TSL:1	n.204T>C		non_coding_transcript_exon	Exon 3 of 3
	TGFB1	ENST00000890114.1		c.673T>C	p.Cys225Arg	missense	Exon 4 of 7	ENSP00000560173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diaphyseal dysplasia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.087	D
PhyloP100		4.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.95
MutPred		0.80		Gain of disorder (P = 0.0054)
MVP		0.89
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs104894719; hg19: chr19-41848114;