rs1381354900

Variant names:

• chr9-99105294-G-T
• rs1381354900
• NM_004612.4:c.89G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004612.4(TGFBR1):​c.89G>T​(p.Gly30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 991,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.402
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17814082).
• BS2: High AC in GnomAdExome4 at 18 AD,Unknown 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.89G>T	p.Gly30Val	missense	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.89G>T	p.Gly30Val	missense	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.89G>T	p.Gly30Val	missense	Exon 1 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.89G>T	p.Gly30Val	missense	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.89G>T	p.Gly30Val	missense	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.89G>T	p.Gly30Val	missense	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000457

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 18 AN: 845742 Hom.: 0 Cov.: 31 AF XY: 0.0000204 AC XY: 8 AN XY: 392584

African (AFR) AF: 0.00 AC: 0 AN: 16032

American (AMR) AF: 0.00 AC: 0 AN: 1358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4162

South Asian (SAS) AF: 0.00 AC: 0 AN: 17412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1680

European-Non Finnish (NFE) AF: 0.0000221 AC: 17 AN: 770328

Other (OTH) AF: 0.0000357 AC: 1 AN: 28016

GnomAD4 genome AF: 0.0000206 AC: 3 AN: 145928 Hom.: 0 Cov.: 32 AF XY: 0.0000282 AC XY: 2 AN XY: 71000

African (AFR) AF: 0.00 AC: 0 AN: 40784

American (AMR) AF: 0.00 AC: 0 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5050

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000457 AC: 3 AN: 65642

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial thoracic aortic aneurysm and aortic dissection (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.40
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.22
Sift	Benign	0.55	T
Sift4G	Benign	0.45	T
Polyphen		0.18	B
Vest4		0.11
MutPred		0.42		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.67
MPC		0.64
ClinPred		0.065	T
GERP RS		1.7
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.058
gMVP		0.41
Mutation Taster		=77/23	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: rs1381354900; hg19: chr9-101867576;