9-99128971-A-T

Variant names:

• chr9-99128971-A-T
• rs111513627
• NM_004612.4:c.214A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001306210.2(TGFBR1):​c.214A>T​(p.Ile72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000256 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I72V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TGFBR1 NM_001306210.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 4.10
• Publications: 5 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1676732).
• BP6: Variant 9-99128971-A-T is Benign according to our data. Variant chr9-99128971-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178136.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000263 (384/1461712) while in subpopulation NFE AF = 0.00033 (367/1111926). AF 95% confidence interval is 0.000302. There are 0 homozygotes in GnomAdExome4. There are 186 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306210.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	NM_004612.4	MANE Select	c.214A>T	p.Ile72Leu	missense	Exon 2 of 9	NP_004603.1
	TGFBR1	NM_001306210.2		c.214A>T	p.Ile72Leu	missense	Exon 2 of 9	NP_001293139.1
	TGFBR1	NM_001407416.1		c.214A>T	p.Ile72Leu	missense	Exon 2 of 8	NP_001394345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.214A>T	p.Ile72Leu	missense	Exon 2 of 9	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.214A>T	p.Ile72Leu	missense	Exon 2 of 9	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.214A>T	p.Ile72Leu	missense	Exon 2 of 8	ENSP00000364129.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000338

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 250904 AF XY: 0.000214

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 186 AN XY: 727152

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.000179 AC: 8 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000330 AC: 367 AN: 1111926

Other (OTH) AF: 0.000116 AC: 7 AN: 60380

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74348

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Familial thoracic aortic aneurysm and aortic dissection (4)
-	3	1	not provided (4)
-	1	1	not specified (2)
-	1	-	Ehlers-Danlos syndrome (1)
-	1	-	TGFBR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.69	N
PhyloP100		4.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0	B
Vest4		0.35
MutPred		0.52		Loss of catalytic residue at L77 (P = 0.062)
MVP		0.61
MPC		0.52
ClinPred		0.12	T
GERP RS		6.1
Varity_R		0.66
gMVP		0.88
Mutation Taster		=74/26	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: rs111513627; hg19: chr9-101891253;