1-91797317-T-C

Variant names:

• chr1-91797317-T-C
• rs2810904
• NM_003243.5:c.216A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003243.5(TGFBR3):​c.216A>G​(p.Ala72Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,988 control chromosomes in the GnomAD database, including 346,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34618 hom., cov: 33)
  • Exomes 𝑓: 0.65 (311737 hom.)
• Consequence: TGFBR3 NM_003243.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.30
• Publications: 21 publications found

Genes affected

TGFBR3 (HGNC:11774): (transforming growth factor beta receptor 3) This locus encodes the transforming growth factor (TGF)-beta type III receptor. The encoded receptor is a membrane proteoglycan that often functions as a co-receptor with other TGF-beta receptor superfamily members. Ectodomain shedding produces soluble TGFBR3, which may inhibit TGFB signaling. Decreased expression of this receptor has been observed in various cancers. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[provided by RefSeq, Sep 2010]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-91797317-T-C is Benign according to our data. Variant chr1-91797317-T-C is described in ClinVar as Benign. ClinVar VariationId is 1276034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR3	NM_003243.5	c.216A>G	p.Ala72Ala	synonymous_variant	Exon 3 of 17	ENST00000212355.9	NP_003234.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR3	ENST00000212355.9	c.216A>G	p.Ala72Ala	synonymous_variant	Exon 3 of 17	1	NM_003243.5	ENSP00000212355.4

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102201 AN: 152038 Hom.: 34570 Cov.: 33

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.660 AC: 165761 AN: 251248 AF XY: 0.659

Gnomad AFR exome AF: 0.755

Gnomad AMR exome AF: 0.643

Gnomad ASJ exome AF: 0.631

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.605

Gnomad NFE exome AF: 0.639

Gnomad OTH exome AF: 0.648

GnomAD4 exome AF: 0.651 AC: 952340 AN: 1461832 Hom.: 311737 Cov.: 65 AF XY: 0.652 AC XY: 474292 AN XY: 727214

African (AFR) AF: 0.754 AC: 25243 AN: 33480

American (AMR) AF: 0.645 AC: 28856 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 16401 AN: 26130

East Asian (EAS) AF: 0.828 AC: 32870 AN: 39700

South Asian (SAS) AF: 0.687 AC: 59279 AN: 86256

European-Finnish (FIN) AF: 0.606 AC: 32369 AN: 53416

Middle Eastern (MID) AF: 0.699 AC: 4025 AN: 5758

European-Non Finnish (NFE) AF: 0.642 AC: 713505 AN: 1111974

Other (OTH) AF: 0.659 AC: 39792 AN: 60396

GnomAD4 genome AF: 0.672 AC: 102303 AN: 152156 Hom.: 34618 Cov.: 33 AF XY: 0.671 AC XY: 49906 AN XY: 74398

African (AFR) AF: 0.747 AC: 31002 AN: 41520

American (AMR) AF: 0.660 AC: 10094 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2121 AN: 3470

East Asian (EAS) AF: 0.786 AC: 4060 AN: 5164

South Asian (SAS) AF: 0.678 AC: 3268 AN: 4822

European-Finnish (FIN) AF: 0.597 AC: 6320 AN: 10592

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43369 AN: 67972

Other (OTH) AF: 0.661 AC: 1397 AN: 2114

Alfa AF: 0.650 Hom.: 16463

Bravo AF: 0.681

Asia WGS AF: 0.709 AC: 2470 AN: 3478

EpiCase AF: 0.642

EpiControl AF: 0.638

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

TGFBR3-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.082
DANN	Benign	0.50
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2810904; hg19: chr1-92262874; COSMIC: COSV53031907; COSMIC: COSV53031907;