3-30691909-TTATATATATA-TTATATATATATATA

Position:

• chr3-30691909-TTATATATATA-TTATATATATATATA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003242.6(TGFBR2):​c.*326_*329dupATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.163

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00272 (401/147342) while in subpopulation AFR AF= 0.00852 (340/39884). AF 95% confidence interval is 0.00778. There are 1 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 401 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.*326_*329dupATAT		3_prime_UTR_variant	7/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.*326_*329dupATAT		3_prime_UTR_variant	7/7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.*326_*329dupATAT		3_prime_UTR_variant	8/8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.3626_3629dupATAT		non_coding_transcript_exon_variant	7/7
TGFBR2	ENST00000673203.1	n.908_911dupATAT		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 399 AN: 147306 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00196

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000343

Gnomad OTH AF: 0.00249

GnomAD4 exome AF: 0.000390 AC: 39 AN: 100082 Hom.: 0 Cov.: 0 AF XY: 0.000343 AC XY: 17 AN XY: 49616

Gnomad4 AFR exome AF: 0.00271

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000213

Gnomad4 EAS exome AF: 0.000162

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00272 AC: 401 AN: 147342 Hom.: 1 Cov.: 0 AF XY: 0.00252 AC XY: 181 AN XY: 71732

Gnomad4 AFR AF: 0.00852

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00197

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000343

Gnomad4 OTH AF: 0.00247

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Marfan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2021

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4016180; hg19: chr3-30733401;