chr9-99153794-T-C

Variant names:

• chr9-99153794-T-C
• rs7850895
• NM_004612.4:c.*4489T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004612.4(TGFBR1):​c.*4489T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 206,986 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (466 hom., cov: 33)
  • Exomes 𝑓: 0.066 (153 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.28
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-99153794-T-C is Benign according to our data. Variant chr9-99153794-T-C is described in ClinVar as Benign. ClinVar VariationId is 364185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0823 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.*4489T>C		3_prime_UTR	Exon 9 of 9	NP_004603.1
	TGFBR1	NR_176360.1		n.6105T>C		non_coding_transcript_exon	Exon 9 of 9
	TGFBR1	NR_176361.1		n.6210T>C		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.*4489T>C		3_prime_UTR	Exon 9 of 9	ENSP00000364133.4
	TGFBR1	ENST00000552573.7	TSL:4	c.*4489T>C		3_prime_UTR	Exon 9 of 9	ENSP00000447182.3
	TGFBR1	ENST00000546584.2	TSL:4	c.*4489T>C		3_prime_UTR	Exon 9 of 9	ENSP00000447707.3

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10794 AN: 152202 Hom.: 467 Cov.: 33

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0841

Gnomad OTH AF: 0.0783

GnomAD4 exome AF: 0.0658 AC: 3596 AN: 54666 Hom.: 153 Cov.: 0 AF XY: 0.0687 AC XY: 1751 AN XY: 25470

African (AFR) AF: 0.0560 AC: 138 AN: 2464

American (AMR) AF: 0.0457 AC: 71 AN: 1552

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 216 AN: 3432

East Asian (EAS) AF: 0.00247 AC: 21 AN: 8486

South Asian (SAS) AF: 0.0415 AC: 19 AN: 458

European-Finnish (FIN) AF: 0.139 AC: 17 AN: 122

Middle Eastern (MID) AF: 0.0691 AC: 25 AN: 362

European-Non Finnish (NFE) AF: 0.0830 AC: 2762 AN: 33262

Other (OTH) AF: 0.0722 AC: 327 AN: 4528

GnomAD4 genome AF: 0.0709 AC: 10799 AN: 152320 Hom.: 466 Cov.: 33 AF XY: 0.0714 AC XY: 5321 AN XY: 74490

African (AFR) AF: 0.0549 AC: 2282 AN: 41578

American (AMR) AF: 0.0546 AC: 836 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0360 AC: 174 AN: 4828

European-Finnish (FIN) AF: 0.119 AC: 1267 AN: 10616

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0841 AC: 5720 AN: 68012

Other (OTH) AF: 0.0775 AC: 164 AN: 2116

Alfa AF: 0.0749 Hom.: 926

Bravo AF: 0.0665

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.37
PhyloP100		-1.3
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: rs7850895; hg19: chr9-101916076;