9-99105215-G-T

Variant names:

• chr9-99105215-G-T
• rs1429700300
• NM_004612.4:c.10G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004612.4(TGFBR1):​c.10G>T​(p.Ala4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 148,196 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23653653).

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.10G>T	p.Ala4Ser	missense	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.10G>T	p.Ala4Ser	missense	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.10G>T	p.Ala4Ser	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.10G>T	p.Ala4Ser	missense	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.10G>T	p.Ala4Ser	missense	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.10G>T	p.Ala4Ser	missense	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148196 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: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 933994 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 438654

African (AFR) AF: 0.00 AC: 0 AN: 18410

American (AMR) AF: 0.00 AC: 0 AN: 3622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8702

East Asian (EAS) AF: 0.00 AC: 0 AN: 12618

South Asian (SAS) AF: 0.00 AC: 0 AN: 18272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828540

Other (OTH) AF: 0.00 AC: 0 AN: 33644

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148196 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72236

African (AFR) AF: 0.00 AC: 0 AN: 40912

American (AMR) AF: 0.00 AC: 0 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66640

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.22
Sift	Benign	0.27	T
Sift4G	Benign	0.58	T
Polyphen		0.25	B
Vest4		0.19
MutPred		0.24		Gain of glycosylation at A4 (P = 0.0138)
MVP		0.59
MPC		0.47
ClinPred		0.31	T
GERP RS		2.7
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.045
gMVP		0.36
Mutation Taster		=89/11	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: rs1429700300; hg19: chr9-101867497;