NM_004612.4:c.97+2718T>C

Variant names:

• chr9-99108020-T-C
• rs10988706
• NM_004612.4:c.97+2718T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004612.4(TGFBR1):​c.97+2718T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,130 control chromosomes in the GnomAD database, including 4,089 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4089 hom., cov: 32)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• Publications: 8 publications found

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

TGFBR1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. 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
	TGFBR1	NM_004612.4	MANE Select	c.97+2718T>C		intron	N/A	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.97+2718T>C		intron	N/A	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.97+2718T>C		intron	N/A	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.97+2718T>C		intron	N/A	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.97+2718T>C		intron	N/A	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.97+2718T>C		intron	N/A	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34242 AN: 152012 Hom.: 4077 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.224

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.225 AC: 34298 AN: 152130 Hom.: 4089 Cov.: 32 AF XY: 0.223 AC XY: 16600 AN XY: 74404

African (AFR) AF: 0.253 AC: 10497 AN: 41478

American (AMR) AF: 0.246 AC: 3762 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3462

East Asian (EAS) AF: 0.432 AC: 2236 AN: 5176

South Asian (SAS) AF: 0.224 AC: 1081 AN: 4830

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10606

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13848 AN: 67972

Other (OTH) AF: 0.223 AC: 471 AN: 2114

Alfa AF: 0.221 Hom.: 602

Bravo AF: 0.232

Asia WGS AF: 0.337 AC: 1172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.35
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10988706; hg19: chr9-101870302;