rs1060502044

Variant names:

• chr9-99132665-A-C
• rs1060502044
• NM_004612.4:c.500A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-99132665-A-C
• chr9-99132665-A-T

Variant summary

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

The NM_004612.4(TGFBR1):​c.500A>C​(p.Asp167Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.10
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.500A>C	p.Asp167Ala	missense_variant	Exon 3 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.500A>C	p.Asp167Ala	missense_variant	Exon 3 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jul 02, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR1-related disease. This sequence change replaces aspartic acid with alanine at codon 167 of the TGFBR1 protein (p.Asp167Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. -

Loeys-Dietz syndrome Uncertain:1

May 31, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T;D;.;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D;T;T;D;T;.
Sift4G	Uncertain	0.019	D;D;T;T;D;T;D
Polyphen		0.012	.;.;B;.;.;.;.
Vest4		0.55, 0.60, 0.61
MutPred		0.38		.;.;Loss of disorder (P = 0.0591);.;.;.;.;
MVP		0.82
MPC		0.96
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.22
gMVP		0.84
Mutation Taster		=15/85	disease causing

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: rs1060502044; hg19: chr9-101894947;