rs420549

Variant names:

• chr9-99152591-G-C
• rs420549
• NM_004612.4:c.*3286G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-99152591-G-C
• chr9-99152591-G-T

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.*3286G>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 0.162 in 228,664 control chromosomes in the GnomAD database, including 3,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2071 hom., cov: 32)
  • Exomes 𝑓: 0.17 (1177 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.462
• Publications: 18 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=-0.82).
• BP6: Variant 9-99152591-G-C is Benign according to our data. Variant chr9-99152591-G-C is described in ClinVar as Benign. ClinVar VariationId is 364164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.*3286G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.*3286G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24073 AN: 152046 Hom.: 2073 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.168 AC: 12877 AN: 76500 Hom.: 1177 Cov.: 0 AF XY: 0.170 AC XY: 5997 AN XY: 35374

African (AFR) AF: 0.118 AC: 434 AN: 3664

American (AMR) AF: 0.119 AC: 281 AN: 2360

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 878 AN: 4798

East Asian (EAS) AF: 0.0588 AC: 642 AN: 10914

South Asian (SAS) AF: 0.135 AC: 88 AN: 650

European-Finnish (FIN) AF: 0.175 AC: 53 AN: 302

Middle Eastern (MID) AF: 0.141 AC: 66 AN: 468

European-Non Finnish (NFE) AF: 0.198 AC: 9293 AN: 46972

Other (OTH) AF: 0.179 AC: 1142 AN: 6372

GnomAD4 genome AF: 0.158 AC: 24079 AN: 152164 Hom.: 2071 Cov.: 32 AF XY: 0.152 AC XY: 11276 AN XY: 74394

African (AFR) AF: 0.129 AC: 5365 AN: 41526

American (AMR) AF: 0.131 AC: 2006 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 661 AN: 3470

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5194

South Asian (SAS) AF: 0.104 AC: 504 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1385 AN: 10590

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13555 AN: 67958

Other (OTH) AF: 0.161 AC: 340 AN: 2114

Alfa AF: 0.183 Hom.: 348

Bravo AF: 0.155

Asia WGS AF: 0.0640 AC: 224 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.65
PhyloP100		0.46
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: rs420549; hg19: chr9-101914873;