chr9-99151950-A-C

Position:

• chr9-99151950-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004612.4(TGFBR1):​c.*2645A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 198,876 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (2 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0640

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-99151950-A-C is Benign according to our data. Variant chr9-99151950-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 364148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00629 (958/152284) while in subpopulation NFE AF= 0.00965 (656/68012). AF 95% confidence interval is 0.00903. There are 10 homozygotes in gnomad4. There are 507 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 958 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.*2645A>C		3_prime_UTR_variant	9/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.*2645A>C		3_prime_UTR_variant	9/9	1	NM_004612.4	P4

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 957 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00964

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00528 AC: 246 AN: 46592 Hom.: 2 Cov.: 0 AF XY: 0.00533 AC XY: 115 AN XY: 21578

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.000678

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.00758

Gnomad4 OTH exome AF: 0.00472

GnomAD4 genome AF: 0.00629 AC: 958 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00681 AC XY: 507 AN XY: 74456

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.00965

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00751 Hom.: 3

Bravo AF: 0.00427

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs17724567; hg19: chr9-101914232;