19-41331066-A-T

Variant names:

• chr19-41331066-A-T
• rs1336387628
• NM_000660.7:c.1159T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000660.7(TGFB1):​c.1159T>A​(p.Cys387Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C387G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.06
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics, PanelApp Australia
• inflammatory bowel disease, immunodeficiency, and encephalopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41331066-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488346.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

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.1159T>A	p.Cys387Ser	missense	Exon 7 of 7	NP_000651.3	P01137

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	ENST00000221930.6	TSL:1 MANE Select	c.1159T>A	p.Cys387Ser	missense	Exon 7 of 7	ENSP00000221930.4	A0A499FJK2
	TGFB1	ENST00000890114.1		c.1162T>A	p.Cys388Ser	missense	Exon 7 of 7	ENSP00000560173.1
	TGFB1	ENST00000600196.2	TSL:5	c.1099T>A	p.Cys367Ser	missense	Exon 6 of 6	ENSP00000504008.1	A0A7I2YQL8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000544 AC: 1 AN: 183858 AF XY: 0.0000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420780 Hom.: 0 Cov.: 35 AF XY: 0.00000142 AC XY: 1 AN XY: 703824

African (AFR) AF: 0.00 AC: 0 AN: 32770

American (AMR) AF: 0.00 AC: 0 AN: 38684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 38156

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093620

Other (OTH) AF: 0.00 AC: 0 AN: 58780

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		9.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.91
MutPred		0.87		Gain of disorder (P = 0.0067)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.5
Mutation Taster		=4/96	disease causing

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: rs1336387628; hg19: chr19-41836971;