NM_004612.4:c.97+11679C>A

Variant names:

• chr9-99116981-C-A
• rs2026811
• NM_004612.4:c.97+11679C>A

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+11679C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,008 control chromosomes in the GnomAD database, including 4,886 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 0.25 (4886 hom., cov: 32)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 10 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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	NM_004612.4	MANE Select	c.97+11679C>A		intron	N/A	NP_004603.1
	TGFBR1	NM_001306210.2		c.97+11679C>A		intron	N/A	NP_001293139.1
	TGFBR1	NM_001407416.1		c.97+11679C>A		intron	N/A	NP_001394345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.97+11679C>A		intron	N/A	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.97+11679C>A		intron	N/A	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.97+11679C>A		intron	N/A	ENSP00000364129.2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37322 AN: 151890 Hom.: 4870 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.246 AC: 37382 AN: 152008 Hom.: 4886 Cov.: 32 AF XY: 0.243 AC XY: 18064 AN XY: 74296

African (AFR) AF: 0.298 AC: 12345 AN: 41430

American (AMR) AF: 0.253 AC: 3866 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2419 AN: 5174

South Asian (SAS) AF: 0.231 AC: 1115 AN: 4820

European-Finnish (FIN) AF: 0.154 AC: 1630 AN: 10566

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

European-Non Finnish (NFE) AF: 0.215 AC: 14585 AN: 67950

Other (OTH) AF: 0.237 AC: 502 AN: 2114

Alfa AF: 0.219 Hom.: 2016

Bravo AF: 0.253

Asia WGS AF: 0.361 AC: 1257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.84
DANN	Benign	0.38
PhyloP100		-0.0090
Mutation Taster		=100/0	polymorphism (auto)

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: rs2026811; hg19: chr9-101879263;