rs1365442897

Variant names:

• chr9-99105217-G-A
• rs1365442897
• NM_004612.4:c.12G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-99105217-G-A
• chr9-99105217-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004612.4(TGFBR1):​c.12G>A​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,080,898 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• 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):

• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-99105217-G-A is Benign according to our data. Variant chr9-99105217-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1177254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.12G>A	p.Ala4Ala	synonymous	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.12G>A	p.Ala4Ala	synonymous	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.12G>A	p.Ala4Ala	synonymous	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147634 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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 324 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000750 AC: 7 AN: 933264 Hom.: 0 Cov.: 30 AF XY: 0.00000913 AC XY: 4 AN XY: 438244

African (AFR) AF: 0.00 AC: 0 AN: 18376

American (AMR) AF: 0.00 AC: 0 AN: 3612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8690

East Asian (EAS) AF: 0.00 AC: 0 AN: 12558

South Asian (SAS) AF: 0.00 AC: 0 AN: 18268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2150

European-Non Finnish (NFE) AF: 0.00000845 AC: 7 AN: 828036

Other (OTH) AF: 0.00 AC: 0 AN: 33608

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147634 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71944

African (AFR) AF: 0.00 AC: 0 AN: 40704

American (AMR) AF: 0.00 AC: 0 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66462

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		1.4
PromoterAI		0.0070	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	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: rs1365442897; hg19: chr9-101867499;