1-218345988-A-C

Variant names:

• chr1-218345988-A-C
• rs73110310
• NM_003238.6:c.-714A>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003238.6(TGFB2):​c.-714A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 151,162 control chromosomes in the GnomAD database, including 1,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (1569 hom., cov: 30)
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.389

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-218345988-A-C is Benign according to our data. Variant chr1-218345988-A-C is described in ClinVar as [Benign]. Clinvar id is 295463.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-218345988-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.-714A>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.-714A>C		5_prime_UTR_variant	Exon 1 of 8		NP_001129071.1
TGFB2	NR_138148.2	n.653A>C		non_coding_transcript_exon_variant	Exon 1 of 7
TGFB2	NR_138149.2	n.653A>C		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930	c.-714A>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_003238.6	ENSP00000355897.4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15234 AN: 151044 Hom.: 1556 Cov.: 30

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.0299

Gnomad AMR AF: 0.0537

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0779

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.101 AC: 15284 AN: 151162 Hom.: 1569 Cov.: 30 AF XY: 0.0981 AC XY: 7242 AN XY: 73856

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.0535

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.0803

Gnomad4 SAS AF: 0.0117

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0370

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0218 Hom.: 26

Bravo AF: 0.113

Asia WGS AF: 0.0440 AC: 152 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.3
DANN	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73110310; hg19: chr1-218519330;