NM_001407129.1:c.-58T>A

Variant names:

• chr3-30606547-T-A
• rs1038796042
• NM_001407129.1:c.-58T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001407129.1(TGFBR2):​c.-58T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 284,278 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TGFBR2 NM_001407129.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

TGFBR2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105377015 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407129.1. 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
	TGFBR2	NM_001407129.1		c.-58T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001394058.1
	TGFBR2	NM_001407132.1		c.-58T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001394061.1	A0AAQ5BI06
	TGFBR2	NM_001407129.1		c.-58T>A		5_prime_UTR	Exon 1 of 8	NP_001394058.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000714391.1		c.-55T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000519658.1	A0AAQ5BI03
	TGFBR2	ENST00000714389.1		c.-53T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000519656.1	A0AAQ5BI06
	TGFBR2	ENST00000714390.1		c.-58T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000519657.1	A0AAQ5BI06

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000227 AC: 3 AN: 132130 Hom.: 0 Cov.: 0 AF XY: 0.0000156 AC XY: 1 AN XY: 64064

African (AFR) AF: 0.00 AC: 0 AN: 5094

American (AMR) AF: 0.00 AC: 0 AN: 3740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6378

East Asian (EAS) AF: 0.00 AC: 0 AN: 14796

South Asian (SAS) AF: 0.00 AC: 0 AN: 1138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 760

European-Non Finnish (NFE) AF: 0.0000241 AC: 2 AN: 83002

Other (OTH) AF: 0.000103 AC: 1 AN: 9718

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Uncertain significance/Uncertain risk allele

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Diabetic retinopathy (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		2.2
PromoterAI		-0.14	Neutral

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: rs1038796042; hg19: chr3-30648039;