rs11466595

Variant names:

• chr1-91720178-G-A
• rs11466595
• NM_003243.5:c.1128C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003243.5(TGFBR3):​c.1128C>T​(p.Ile376Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,612,964 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (102 hom.)
• Consequence: TGFBR3 NM_003243.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-91720178-G-A is Benign according to our data. Variant chr1-91720178-G-A is described in ClinVar as Benign. ClinVar VariationId is 773411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS2: High AC in GnomAd4 at 1157 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.1128C>T	p.Ile376Ile	synonymous	Exon 9 of 17	NP_003234.2	Q03167-1
	TGFBR3	NM_001195683.2		c.1125C>T	p.Ile375Ile	synonymous	Exon 9 of 17	NP_001182612.1	A0A0A8KWK3
	TGFBR3	NM_001195684.1		c.1125C>T	p.Ile375Ile	synonymous	Exon 10 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.1128C>T	p.Ile376Ile	synonymous	Exon 9 of 17	ENSP00000212355.4	Q03167-1
	TGFBR3	ENST00000525962.5	TSL:1	c.1128C>T	p.Ile376Ile	synonymous	Exon 8 of 16	ENSP00000436127.1	Q03167-1
	TGFBR3	ENST00000370399.6	TSL:1	c.1125C>T	p.Ile375Ile	synonymous	Exon 10 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1157 AN: 152228 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00746 AC: 1838 AN: 246308 AF XY: 0.00798

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.00442

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.0106 AC: 15487 AN: 1460618 Hom.: 102 Cov.: 34 AF XY: 0.0106 AC XY: 7706 AN XY: 726510

African (AFR) AF: 0.00149 AC: 50 AN: 33472

American (AMR) AF: 0.00247 AC: 110 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39618

South Asian (SAS) AF: 0.00629 AC: 542 AN: 86110

European-Finnish (FIN) AF: 0.0109 AC: 580 AN: 53218

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5718

European-Non Finnish (NFE) AF: 0.0122 AC: 13563 AN: 1111468

Other (OTH) AF: 0.00860 AC: 519 AN: 60324

GnomAD4 genome AF: 0.00759 AC: 1157 AN: 152346 Hom.: 7 Cov.: 33 AF XY: 0.00746 AC XY: 556 AN XY: 74498

African (AFR) AF: 0.00216 AC: 90 AN: 41576

American (AMR) AF: 0.00287 AC: 44 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00662 AC: 32 AN: 4832

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0122 AC: 830 AN: 68042

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00951 Hom.: 6

Bravo AF: 0.00691

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	TGFBR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.1
DANN	Benign	0.69
PhyloP100		1.1
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: rs11466595; hg19: chr1-92185735; COSMIC: COSV99283371;