rs1331965992

Variant names:

• chr9-99105216-C-A
• rs1331965992
• NM_004612.4:c.11C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-99105216-C-A
• chr9-99105216-C-G
• chr9-99105216-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004612.4(TGFBR1):​c.11C>A​(p.Ala4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000107 in 930,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.647
• 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33852702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 930962 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 436948

African (AFR) AF: 0.00 AC: 0 AN: 18312

American (AMR) AF: 0.00 AC: 0 AN: 3554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8602

East Asian (EAS) AF: 0.00 AC: 0 AN: 12344

South Asian (SAS) AF: 0.00 AC: 0 AN: 18232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2146

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826586

Other (OTH) AF: 0.00 AC: 0 AN: 33438

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.42	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		0.65
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.15	T;D;T
Sift4G	Benign	0.19	T;D;T
Polyphen		0.93	P;D;.
Vest4		0.32
MutPred		0.33		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.70
MPC		0.60
ClinPred		0.68	D
GERP RS		0.66
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.15
gMVP		0.63
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1331965992; hg19: chr9-101867498;