rs138514914

Variant names:

• chr1-218405179-G-A
• rs138514914
• NM_003238.6:c.357G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-218405179-G-A
• chr1-218405179-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001135599.4(TGFB2):​c.441G>A​(p.Pro147Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,582,866 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: TGFB2 NM_001135599.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0260
• Publications: 3 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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-218405179-G-A is Benign according to our data. Variant chr1-218405179-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000546 (83/151960) while in subpopulation SAS AF = 0.00104 (5/4824). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 83 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135599.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	NM_003238.6	MANE Select	c.357G>A	p.Pro119Pro	synonymous	Exon 2 of 7	NP_003229.1
	TGFB2	NM_001135599.4		c.441G>A	p.Pro147Pro	synonymous	Exon 3 of 8	NP_001129071.1
	TGFB2	NR_138148.2		n.1723G>A		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.357G>A	p.Pro119Pro	synonymous	Exon 2 of 7	ENSP00000355897.4
	TGFB2	ENST00000366929.4	TSL:1	c.441G>A	p.Pro147Pro	synonymous	Exon 3 of 8	ENSP00000355896.4
	TGFB2	ENST00000488793.1	TSL:3	n.21G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000945 AC: 226 AN: 239280 AF XY: 0.00102

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000539 AC: 771 AN: 1430906 Hom.: 7 Cov.: 30 AF XY: 0.000620 AC XY: 438 AN XY: 706956

African (AFR) AF: 0.00 AC: 0 AN: 32404

American (AMR) AF: 0.0000239 AC: 1 AN: 41846

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 425 AN: 24982

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39076

South Asian (SAS) AF: 0.00143 AC: 119 AN: 83224

European-Finnish (FIN) AF: 0.0000568 AC: 3 AN: 52810

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5590

European-Non Finnish (NFE) AF: 0.000125 AC: 136 AN: 1092136

Other (OTH) AF: 0.00143 AC: 84 AN: 58838

GnomAD4 genome AF: 0.000546 AC: 83 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74194

African (AFR) AF: 0.0000484 AC: 2 AN: 41352

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68004

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.000574

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Loeys-Dietz syndrome 4 (4)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.64
PhyloP100		0.026
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138514914; hg19: chr1-218578521; COSMIC: COSV100860490;