rs104894722

chr19-41342215-A-Cchr19-41342215-A-Gchr19-41342215-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5

The NM_000660.7(TGFB1):c.667T>G(p.Cys223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C223R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.05

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 13 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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000660.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41342215-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12533.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 19-41342215-A-C is Pathogenic according to our data. Variant chr19-41342215-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12530.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7	c.667T>G	p.Cys223Gly	missense_variant	4/7	ENST00000221930.6
TGFB1	XM_011527242.3	c.667T>G	p.Cys223Gly	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB1	ENST00000221930.6	c.667T>G	p.Cys223Gly	missense_variant	4/7	1	NM_000660.7	P1
TGFB1	ENST00000597453.1	n.198T>G		non_coding_transcript_exon_variant	3/3	1
TGFB1	ENST00000600196.2	c.667T>G	p.Cys223Gly	missense_variant	4/6	5
TGFB1	ENST00000677934.1	c.634+2532T>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diaphyseal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	27
Dann	Uncertain	0.98
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.064	T
Vest4		0.86
MutPred		0.85		Gain of disorder (P = 0.0052);
MVP		0.88
MPC		1.6
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894722; hg19: chr19-41848120;