chr1-91722095-A-G

Variant names:

• chr1-91722095-A-G
• rs149079126
• NM_003243.5:c.935T>C

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.935T>C​(p.Met312Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000537 in 1,613,900 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: TGFBR3 NM_003243.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.12
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069850683).
• BP6: Variant 1-91722095-A-G is Benign according to our data. Variant chr1-91722095-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 561334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 88 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.935T>C	p.Met312Thr	missense	Exon 8 of 17	NP_003234.2	Q03167-1
	TGFBR3	NM_001195683.2		c.935T>C	p.Met312Thr	missense	Exon 8 of 17	NP_001182612.1	A0A0A8KWK3
	TGFBR3	NM_001195684.1		c.935T>C	p.Met312Thr	missense	Exon 9 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.935T>C	p.Met312Thr	missense	Exon 8 of 17	ENSP00000212355.4	Q03167-1
	TGFBR3	ENST00000525962.5	TSL:1	c.935T>C	p.Met312Thr	missense	Exon 7 of 16	ENSP00000436127.1	Q03167-1
	TGFBR3	ENST00000370399.6	TSL:1	c.935T>C	p.Met312Thr	missense	Exon 9 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000781 AC: 196 AN: 251008 AF XY: 0.000804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000533 AC: 779 AN: 1461616 Hom.: 4 Cov.: 31 AF XY: 0.000571 AC XY: 415 AN XY: 727094

African (AFR) AF: 0.000388 AC: 13 AN: 33474

American (AMR) AF: 0.000738 AC: 33 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 303 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5764

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1111894

Other (OTH) AF: 0.00156 AC: 94 AN: 60384

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74468

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000981 AC: 15 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68016

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

Alfa AF: 0.000904 Hom.: 0

Bravo AF: 0.000638

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000437

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.064
Sift	Benign	0.40	T
Sift4G	Benign	0.52	T
Polyphen		0.020	B
Vest4		0.29
MVP		0.53
MPC		0.26
ClinPred		0.039	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.49
Mutation Taster		=99/1	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: rs149079126; hg19: chr1-92187652;