rs7871490

Variant names:

• chr9-99151408-T-G
• rs7871490
• NM_004612.4:c.*2103T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004612.4(TGFBR1):​c.*2103T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 222,492 control chromosomes in the GnomAD database, including 1,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1427 hom., cov: 28)
  • Exomes 𝑓: 0.13 (499 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.212
• Publications: 9 publications found

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

TGFBR1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. 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
	TGFBR1	NM_004612.4	MANE Select	c.*2103T>G		3_prime_UTR	Exon 9 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.*2103T>G		3_prime_UTR	Exon 9 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.*2103T>G		3_prime_UTR	Exon 8 of 8	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.*2103T>G		3_prime_UTR	Exon 9 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.*2103T>G		3_prime_UTR	Exon 9 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.*2103T>G		3_prime_UTR	Exon 8 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19146 AN: 148010 Hom.: 1422 Cov.: 28

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.110

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.138

GnomAD4 exome AF: 0.127 AC: 9489 AN: 74444 Hom.: 499 Cov.: 0 AF XY: 0.127 AC XY: 4357 AN XY: 34368

African (AFR) AF: 0.0624 AC: 223 AN: 3572

American (AMR) AF: 0.203 AC: 469 AN: 2306

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 536 AN: 4816

East Asian (EAS) AF: 0.0200 AC: 211 AN: 10524

South Asian (SAS) AF: 0.115 AC: 73 AN: 636

European-Finnish (FIN) AF: 0.125 AC: 7 AN: 56

Middle Eastern (MID) AF: 0.138 AC: 62 AN: 450

European-Non Finnish (NFE) AF: 0.154 AC: 7070 AN: 45900

Other (OTH) AF: 0.136 AC: 838 AN: 6184

GnomAD4 genome AF: 0.129 AC: 19156 AN: 148048 Hom.: 1427 Cov.: 28 AF XY: 0.132 AC XY: 9494 AN XY: 71988

African (AFR) AF: 0.0573 AC: 2325 AN: 40568

American (AMR) AF: 0.191 AC: 2849 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 424 AN: 3458

East Asian (EAS) AF: 0.0204 AC: 105 AN: 5136

South Asian (SAS) AF: 0.0914 AC: 434 AN: 4746

European-Finnish (FIN) AF: 0.203 AC: 1809 AN: 8902

Middle Eastern (MID) AF: 0.105 AC: 30 AN: 286

European-Non Finnish (NFE) AF: 0.161 AC: 10775 AN: 67060

Other (OTH) AF: 0.136 AC: 280 AN: 2060

Alfa AF: 0.169 Hom.: 197

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Loeys-Dietz syndrome (1)
-	1	-	Loeys-Dietz syndrome 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.81
DANN	Benign	0.17
PhyloP100		-0.21
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: rs7871490; hg19: chr9-101913690; COSMIC: COSV66624780; COSMIC: COSV66624780;