NM_004612.4:c.344-430T>G

Variant names:

• chr9-99132079-T-G
• rs10819639
• NM_004612.4:c.344-430T>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.344-430T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,018 control chromosomes in the GnomAD database, including 3,319 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3319 hom., cov: 31)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.81
• Publications: 6 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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.344-430T>G		intron_variant	Intron 2 of 8	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.344-430T>G		intron_variant	Intron 2 of 8	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30359 AN: 151900 Hom.: 3318 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.200 AC: 30379 AN: 152018 Hom.: 3319 Cov.: 31 AF XY: 0.194 AC XY: 14378 AN XY: 74304

African (AFR) AF: 0.153 AC: 6349 AN: 41476

American (AMR) AF: 0.163 AC: 2494 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 790 AN: 3470

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5194

South Asian (SAS) AF: 0.197 AC: 951 AN: 4818

European-Finnish (FIN) AF: 0.190 AC: 1998 AN: 10530

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17018 AN: 67928

Other (OTH) AF: 0.209 AC: 440 AN: 2110

Alfa AF: 0.226 Hom.: 540

Bravo AF: 0.193

Asia WGS AF: 0.103 AC: 359 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.1
DANN	Benign	0.28
PhyloP100		-2.8
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: rs10819639; hg19: chr9-101894361;