rs104894719

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• 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

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_000660.7 (TGFB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a strand (size 15) in uniprot entity TGFB1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 id is 12528.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-41342209-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.673T>C	p.Cys225Arg	missense_variant	Exon 4 of 7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.673T>C	p.Cys225Arg	missense_variant	Exon 4 of 7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.673T>C	p.Cys225Arg	missense_variant	Exon 4 of 7	1	NM_000660.7	ENSP00000221930.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Diaphyseal dysplasia Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 13, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894719; hg19: chr19-41848114;