rs148176750

Variant names:

• chr9-99132580-A-G
• rs148176750
• NM_004612.4:c.415A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001306210.2(TGFBR1):​c.427A>G​(p.Ile143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: TGFBR1 NM_001306210.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 1.26
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008873701).
• BP6: Variant 9-99132580-A-G is Benign according to our data. Variant chr9-99132580-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177810.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000204 (31/152314) while in subpopulation AMR AF = 0.000654 (10/15296). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306210.2. 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.415A>G	p.Ile139Val	missense	Exon 3 of 9	NP_004603.1
	TGFBR1	NM_001306210.2		c.427A>G	p.Ile143Val	missense	Exon 3 of 9	NP_001293139.1
	TGFBR1	NM_001407416.1		c.427A>G	p.Ile143Val	missense	Exon 3 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.415A>G	p.Ile139Val	missense	Exon 3 of 9	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.427A>G	p.Ile143Val	missense	Exon 3 of 9	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.343+3480A>G		intron	N/A	ENSP00000364129.2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251066 AF XY: 0.000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1461870 Hom.: 1 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 141 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112004

Other (OTH) AF: 0.000480 AC: 29 AN: 60390

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	3	not provided (3)
-	1	1	not specified (2)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Loeys-Dietz syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.087
Sift	Benign	0.32	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.24
MPC		0.43
ClinPred		0.012	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.47
Mutation Taster		=93/7	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: rs148176750; hg19: chr9-101894862; COSMIC: COSV66626059;