rs11466365

Variant names:

• chr1-218345686-C-T
• rs11466365
• NM_003238.6:c.-1016C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003238.6(TGFB2):​c.-1016C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 152,226 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0640
• Publications: 0 publications found

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2-AS1 (HGNC:50628): (TGFB2 antisense RNA 1 (head to head))

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-218345686-C-T is Benign according to our data. Variant chr1-218345686-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 295459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1528/152226) while in subpopulation AFR AF = 0.0333 (1383/41558). AF 95% confidence interval is 0.0318. There are 22 homozygotes in GnomAd4. There are 744 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1528 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003238.6. 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
	TGFB2	NM_003238.6	MANE Select	c.-1016C>T		5_prime_UTR	Exon 1 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.-1016C>T		5_prime_UTR	Exon 1 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.351C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.-1016C>T		5_prime_UTR	Exon 1 of 7	ENSP00000355897.4	P61812-1
	TGFB2-AS1	ENST00000414452.3	TSL:3	n.365G>A		non_coding_transcript_exon	Exon 1 of 3
	TGFB2-AS1	ENST00000687392.2		n.302G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1524 AN: 152108 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0105

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 428 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 328

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 356

Other (OTH) AF: 0.00 AC: 0 AN: 24

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152226 Hom.: 22 Cov.: 32 AF XY: 0.0100 AC XY: 744 AN XY: 74418

African (AFR) AF: 0.0333 AC: 1383 AN: 41558

American (AMR) AF: 0.00679 AC: 104 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67996

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00568 Hom.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Loeys-Dietz syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.4
DANN	Benign	0.91
PhyloP100		0.064
PromoterAI		0.035	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11466365; hg19: chr1-218519028;