chr9-99144883-A-C

Variant names:

• chr9-99144883-A-C
• rs7861780
• NM_004612.4:c.1125A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004612.4(TGFBR1):​c.1125A>C​(p.Thr375Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,796 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T375T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (21 hom.)
• Consequence: TGFBR1 NM_004612.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.587
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-99144883-A-C is Benign according to our data. Variant chr9-99144883-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.587 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00289 (441/152358) while in subpopulation SAS AF = 0.00435 (21/4830). AF 95% confidence interval is 0.00385. There are 3 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 441 AD gene.

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.1125A>C	p.Thr375Thr	synonymous	Exon 6 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.1137A>C	p.Thr379Thr	synonymous	Exon 6 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.969A>C	p.Thr323Thr	synonymous	Exon 5 of 8	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.1125A>C	p.Thr375Thr	synonymous	Exon 6 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.1137A>C	p.Thr379Thr	synonymous	Exon 6 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.894A>C	p.Thr298Thr	synonymous	Exon 5 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152240 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00398 AC: 1000 AN: 251038 AF XY: 0.00405

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00545

Gnomad OTH exome AF: 0.00590

GnomAD4 exome AF: 0.00445 AC: 6503 AN: 1461438 Hom.: 21 Cov.: 31 AF XY: 0.00458 AC XY: 3328 AN XY: 727026

African (AFR) AF: 0.000478 AC: 16 AN: 33462

American (AMR) AF: 0.00436 AC: 195 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00437 AC: 377 AN: 86254

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53326

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5762

European-Non Finnish (NFE) AF: 0.00489 AC: 5436 AN: 1111760

Other (OTH) AF: 0.00439 AC: 265 AN: 60374

GnomAD4 genome AF: 0.00289 AC: 441 AN: 152358 Hom.: 3 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74506

African (AFR) AF: 0.000866 AC: 36 AN: 41586

American (AMR) AF: 0.00386 AC: 59 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00447 Hom.: 4

Bravo AF: 0.00320

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00393

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Familial thoracic aortic aneurysm and aortic dissection (6)
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	3	Loeys-Dietz syndrome (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Loeys-Dietz syndrome 1 (1)
-	-	1	Multiple self-healing squamous epithelioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		0.59
Mutation Taster		=90/10	polymorphism

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: rs7861780; hg19: chr9-101907165;