NM_003243.5:c.55A>G

Variant names:

• chr1-91861477-T-C
• rs147586574
• NM_003243.5:c.55A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003243.5(TGFBR3):​c.55A>G​(p.Thr19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,611,870 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (33 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.176
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033077002).
• BP6: Variant 1-91861477-T-C is Benign according to our data. Variant chr1-91861477-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 547813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 560 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003243.5. 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
	TGFBR3	NM_003243.5	MANE Select	c.55A>G	p.Thr19Ala	missense	Exon 2 of 17	NP_003234.2	Q03167-1
	TGFBR3	NM_001195683.2		c.55A>G	p.Thr19Ala	missense	Exon 2 of 17	NP_001182612.1	A0A0A8KWK3
	TGFBR3	NM_001195684.1		c.55A>G	p.Thr19Ala	missense	Exon 3 of 18	NP_001182613.1	A0A0A8KWK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR3	ENST00000212355.9	TSL:1 MANE Select	c.55A>G	p.Thr19Ala	missense	Exon 2 of 17	ENSP00000212355.4	Q03167-1
	TGFBR3	ENST00000525962.5	TSL:1	c.55A>G	p.Thr19Ala	missense	Exon 1 of 16	ENSP00000436127.1	Q03167-1
	TGFBR3	ENST00000370399.6	TSL:1	c.55A>G	p.Thr19Ala	missense	Exon 3 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152202 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00404 AC: 1016 AN: 251438 AF XY: 0.00395

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00306 AC: 4463 AN: 1459550 Hom.: 33 Cov.: 29 AF XY: 0.00297 AC XY: 2155 AN XY: 726298

African (AFR) AF: 0.000299 AC: 10 AN: 33412

American (AMR) AF: 0.000179 AC: 8 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86200

European-Finnish (FIN) AF: 0.0284 AC: 1517 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00251 AC: 2781 AN: 1109964

Other (OTH) AF: 0.00240 AC: 145 AN: 60332

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152320 Hom.: 7 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74496

African (AFR) AF: 0.000385 AC: 16 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00231 Hom.: 3

Bravo AF: 0.00128

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00368 AC: 447

EpiCase AF: 0.00234

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	-	1	TGFBR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.7
DANN	Benign	0.25
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.18
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.0070
Sift	Benign	0.10	T
Sift4G	Benign	0.82	T
Polyphen		0.10	B
Vest4		0.16
MVP		0.45
MPC		0.22
ClinPred		0.0042	T
GERP RS		1.6
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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: rs147586574; hg19: chr1-92327034; COSMIC: COSV105820764;