chr19-41352753-C-T

Variant names:

• chr19-41352753-C-T
• rs761100949
• NM_000660.7:c.292G>A
• TGFB1 p.Glu98Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM1PM2BP4

The NM_000660.7(TGFB1):c.292G>A (p.Glu98Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,613,156 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E98Q: Uncertain_significance (ClinVar VariationId 3020729, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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.292G>A p.Glu98Lys	missense	Exon 1 of 7	Prot: NP_000651.3 UniProt:

TGFB1 NM_000660.7

MANE Select

HGVSc / HGVSpc.292G>Ap.Glu98Lys

Exon rankExon 1 of 7

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.292G>A p.Glu98Lys	missense	Exon 1 of 7	Prot: ENSP00000221930.4 UniProt:
	TMEM91 ENST00000539627.5	TSL:1	c.-30+1551C>T	intron	Intron 1 of 2	Prot: ENSP00000441900.1 UniProt:
	TMEM91 ENST00000966284.1		c.-420C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	Prot: ENSP00000636343.1 UniProt:

TGFB1 ENST00000221930.6

TSL:1MANE Select

HGVSc / HGVSpc.292G>Ap.Glu98Lys

Exon rankExon 1 of 7

missense

Prot: ENSP00000221930.4UniProt: A0A499FJK2P01137

TMEM91 ENST00000539627.5

TSL:1

HGVSc / HGVSpc.-30+1551C>T

Exon rankIntron 1 of 2

intron

Prot: ENSP00000441900.1UniProt: F5GWC9

TMEM91 ENST00000966284.1

HGVSc / HGVSpc.-420C>T

Exon rankExon 1 of 4

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000636343.1UniProt: Q6ZNR0-1

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152128	Cov:31
GnomAD2 exomes	AF: 0.00000405	AC:1	Hom:	AN:247200	Cov:
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461028	Cov:32
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152128	Cov:31
TOPMed (Bravo)	AF: 0.0000151	AC:4	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000469	AC:1	Hom:0	AN:21310	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.30	N
FuncVEP CTI	Benign	0.024
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	89/11	polymorphism
PhyloP100	Benign	0.54
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.68	T
PromoterAI	N/A	0.040	Neutral
PROVEAN	Benign	-0.94	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.18
Sift	Benign	0.099	T
Sift4G	Benign	0.30	T
VESM-3B	Benign	-7.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs761100949;

hg19: chr19-41858658;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar