1-91708764-G-A

Position:

• chr1-91708764-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003243.5(TGFBR3):​c.2186C>T​(p.Ala729Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR3	NM_003243.5	c.2186C>T	p.Ala729Val	missense_variant	14/17	ENST00000212355.9	NP_003234.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR3	ENST00000212355.9	c.2186C>T	p.Ala729Val	missense_variant	14/17	1	NM_003243.5	ENSP00000212355	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.2186C>T (p.A729V) alteration is located in exon 14 (coding exon 13) of the TGFBR3 gene. This alteration results from a C to T substitution at nucleotide position 2186, causing the alanine (A) at amino acid position 729 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;.;.;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.29	T;T;T;T
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.70
MutPred		0.38		Gain of loop (P = 0.0502);.;Gain of loop (P = 0.0502);.;
MVP		0.74
MPC		0.44
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-92174321;