3-30650235-T-G

Position:

• chr3-30650235-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003242.6(TGFBR2):​c.264-35T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,598,726 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (27 hom.)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.581

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-30650235-T-G is Benign according to our data. Variant chr3-30650235-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 259012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00866 (1317/152136) while in subpopulation AFR AF= 0.0305 (1267/41502). AF 95% confidence interval is 0.0291. There are 17 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.264-35T>G		intron_variant		ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.264-35T>G		intron_variant		1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.339-35T>G		intron_variant		1
TGFBR2	ENST00000672866.1	n.1860-35T>G		intron_variant, non_coding_transcript_variant
TGFBR2	ENST00000673250.1	n.388-35T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1317 AN: 152018 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

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: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00220 AC: 549 AN: 249764 Hom.: 8 AF XY: 0.00165 AC XY: 223 AN XY: 135066

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000924 AC: 1336 AN: 1446590 Hom.: 27 Cov.: 28 AF XY: 0.000798 AC XY: 575 AN XY: 720762

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000246

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00866 AC: 1317 AN: 152136 Hom.: 17 Cov.: 32 AF XY: 0.00817 AC XY: 608 AN XY: 74394

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00443 Hom.: 1

Bravo AF: 0.0102

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Diabetic retinopathy Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs11466495 with diabetic retinopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs11466495; hg19: chr3-30691727;