chr9-99105225-C-T

Variant names:

• chr9-99105225-C-T
• rs863223802
• NM_004612.4:c.20C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_004612.4(TGFBR1):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000836 in 1,076,616 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.38

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]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19299811).
• BP6: Variant 9-99105225-C-T is Benign according to our data. Variant chr9-99105225-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213860.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.20C>T	p.Ala7Val	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.20C>T	p.Ala7Val	missense_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.0000272 AC: 4 AN: 146856 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: 0.0000453

Gnomad OTH AF: 0.000494

GnomAD4 exome AF: 0.00000538 AC: 5 AN: 929760 Hom.: 0 Cov.: 30 AF XY: 0.00000458 AC XY: 2 AN XY: 436610

African (AFR) AF: 0.00 AC: 0 AN: 18244

American (AMR) AF: 0.00 AC: 0 AN: 3486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8498

East Asian (EAS) AF: 0.00 AC: 0 AN: 12108

South Asian (SAS) AF: 0.00 AC: 0 AN: 18236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2124

European-Non Finnish (NFE) AF: 0.00000605 AC: 5 AN: 825916

Other (OTH) AF: 0.00 AC: 0 AN: 33330

GnomAD4 genome AF: 0.0000272 AC: 4 AN: 146856 Hom.: 0 Cov.: 32 AF XY: 0.0000279 AC XY: 2 AN XY: 71562

African (AFR) AF: 0.00 AC: 0 AN: 40534

American (AMR) AF: 0.00 AC: 0 AN: 14820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66200

Other (OTH) AF: 0.000494 AC: 1 AN: 2024

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jun 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		1.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.11	T;D;T
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.20	B;B;.
Vest4		0.15
MVP		0.75
MPC		0.51
ClinPred		0.18	T
GERP RS		2.7
PromoterAI		0.050	Neutral
Varity_R		0.070
gMVP		0.49
Mutation Taster		=81/19	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

Publications

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Other links and lift over

dbSNP: rs863223802; hg19: chr9-101867507;