9-99112121-A-T

Variant names:

• chr9-99112121-A-T
• rs6478974
• NM_004612.4:c.97+6819A>T

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+6819A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 152,052 control chromosomes in the GnomAD database, including 31,338 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 0.63 (31338 hom., cov: 31)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.66
• Publications: 36 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 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+6819A>T		intron	N/A	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.97+6819A>T		intron	N/A	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.97+6819A>T		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+6819A>T		intron	N/A	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.97+6819A>T		intron	N/A	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.97+6819A>T		intron	N/A	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95271 AN: 151934 Hom.: 31288 Cov.: 31

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.614

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

GnomAD4 genome AF: 0.627 AC: 95375 AN: 152052 Hom.: 31338 Cov.: 31 AF XY: 0.628 AC XY: 46638 AN XY: 74302

African (AFR) AF: 0.832 AC: 34534 AN: 41488

American (AMR) AF: 0.640 AC: 9781 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1772 AN: 3470

East Asian (EAS) AF: 0.661 AC: 3418 AN: 5172

South Asian (SAS) AF: 0.656 AC: 3158 AN: 4814

European-Finnish (FIN) AF: 0.502 AC: 5294 AN: 10554

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35560 AN: 67950

Other (OTH) AF: 0.610 AC: 1288 AN: 2110

Alfa AF: 0.538 Hom.: 12295

Bravo AF: 0.644

Asia WGS AF: 0.675 AC: 2351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.23
DANN	Benign	0.78
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6478974; hg19: chr9-101874403;