chr19-41352751-CTC-TTG

Variant names:

• chr19-41352751-CTC-TTG
• NM_000660.7:c.292_294delGAGinsCAA
• TGFB1 p.Glu98Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_000660.7(TGFB1):c.292_294delGAGinsCAA (p.Glu98Gln) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E98K: Uncertain_significance (ClinVar VariationId 2969295, 1 star); p.E98Q: Uncertain_significance (ClinVar VariationId 3020729, 1 star)

• Frequency: Genomes: not found (cov: 31)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• Publications: 0 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Camurati-Engelmann disease type 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• inflammatory bowel disease, immunodeficiency, and encephalopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Jun 2026]

ENSG00000255730 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 9 pathogenic, 3 benign rare missense variants (OR vs. background: 13.6).; ±8 AA neighbourhood: 0 pathogenic, 0 benign.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000660.7. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGFB1 NM_000660.7	MANE Select	c.292_294delGAGinsCAA p.Glu98Gln	missense	N/A	Prot: NP_000651.3 UniProt:

TGFB1 NM_000660.7

MANE Select

HGVSc / HGVSpc.292_294delGAGinsCAAp.Glu98Gln

Exon rankN/A

missense

Prot: NP_000651.3UniProt: P01137A0A499FJK2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGFB1 ENST00000221930.6	TSL:1MANE Select	c.292_294delGAGinsCAA p.Glu98Gln	missense	N/A	Prot: ENSP00000221930.4 UniProt:
	TMEM91 ENST00000539627.5	TSL:1	c.-30+1549_-30+1551delCTCinsTTG	intron	Intron 1 of 2	Prot: ENSP00000441900.1 UniProt:
	TGFB1 ENST00000890114.1		c.292_294delGAGinsCAA p.Glu98Gln	missense	N/A	Prot: ENSP00000560173.1 UniProt:

TGFB1 ENST00000221930.6

TSL:1MANE Select

HGVSc / HGVSpc.292_294delGAGinsCAAp.Glu98Gln

Exon rankN/A

missense

Prot: ENSP00000221930.4UniProt: A0A499FJK2P01137

TMEM91 ENST00000539627.5

TSL:1

HGVSc / HGVSpc.-30+1549_-30+1551delCTCinsTTG

Exon rankIntron 1 of 2

intron

Prot: ENSP00000441900.1UniProt: F5GWC9

TGFB1 ENST00000890114.1

HGVSc / HGVSpc.292_294delGAGinsCAAp.Glu98Gln

Exon rankN/A

missense

Prot: ENSP00000560173.1UniProt: A0ACI8QUD2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.54

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr19-41858656;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar