Genetic Variant NM_003238.6:c.272G>A (chr1-218346973-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003238.6(TGFB2):c.272G>A(p.Arg91His) variant causes a missense change. The variant allele was found at a frequency of 0.00382 in 1,613,634 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 0.0030 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 18 hom. )

Consequence

TGFB2
NM_003238.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 5.85

Publications

26 publications found

Variant links:

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 links:

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

TGFB2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00862962).

BP6

Variant 1-218346973-G-A is Benign according to our data. Variant chr1-218346973-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152350) while in subpopulation NFE AF = 0.00485 (330/68030). AF 95% confidence interval is 0.00442. There are 4 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 460 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TGFB2	NM_003238.6	MANE Select	c.272G>A	p.Arg91His	missense	Exon 1 of 7	NP_003229.1
TGFB2	NM_001135599.4		c.272G>A	p.Arg91His	missense	Exon 1 of 8	NP_001129071.1
TGFB2	NR_138148.2		n.1638G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.272G>A	p.Arg91His	missense	Exon 1 of 7	ENSP00000355897.4
TGFB2	ENST00000366929.4	TSL:1	c.272G>A	p.Arg91His	missense	Exon 1 of 8	ENSP00000355896.4
TGFB2-AS1	ENST00000774588.1		n.238+656C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00396

AC:

981

AN:

247908

AF XY:

0.00420

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.00231

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00599

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00390

AC:

5700

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

2811

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33466

American (AMR)

AF:

0.00394

AC:

176

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00419

AC:

361

AN:

86216

European-Finnish (FIN)

AF:

0.000938

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00427

AC:

4743

AN:

1111724

Other (OTH)

AF:

0.00419

AC:

253

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

347

694

1041

1388

1735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00302

AC:

460

AN:

152350

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41590

American (AMR)

AF:

0.00359

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00485

AC:

330

AN:

68030

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00501

AC:

ExAC

AF:

0.00437

AC:

530

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Loeys-Dietz syndrome 4 (4)

not provided (4)

not specified (4)

Familial thoracic aortic aneurysm and aortic dissection (2)

Ehlers-Danlos syndrome (1)

Hirschsprung disease, susceptibility to, 1 (1)

Holt-Oram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.038

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.0

PhyloP100

5.9

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.8

REVEL

Benign

0.20

Sift

Benign

0.099

Sift4G

Benign

0.15

Polyphen

0.98

Vest4

0.38

MVP

0.82

MPC

1.9

ClinPred

0.017

GERP RS

5.5

Varity_R

0.18

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over