9-136494732-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017617.5(NOTCH1):c.*1339T>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 0.513 in 398,470 control chromosomes in the GnomAD database, including 53,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.51 (20055 hom., cov: 34)
  • Exomes 𝑓: 0.52 (33922 hom.)
• Consequence: NOTCH1 NM_017617.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.585

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136494732-A-G is Benign according to our data. Variant chr9-136494732-A-G is described in ClinVar as [Benign]. Clinvar id is 1288748.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.*1339T>C		3_prime_UTR_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.*1339T>C		3_prime_UTR_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.*1339T>C		3_prime_UTR_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77297 AN: 151992 Hom.: 20015 Cov.: 34

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.498

GnomAD4 exome AF: 0.516 AC: 127093 AN: 246360 Hom.: 33922 Cov.: 0 AF XY: 0.511 AC XY: 63851 AN XY: 124850

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.557

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.496

GnomAD4 genome AF: 0.509 AC: 77378 AN: 152110 Hom.: 20055 Cov.: 34 AF XY: 0.508 AC XY: 37793 AN XY: 74346

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.724

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.498

Alfa AF: 0.482 Hom.: 16702

Bravo AF: 0.509

Asia WGS AF: 0.458 AC: 1594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2019

This variant is associated with the following publications: (PMID: 30629480) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.23
Dann	Benign	0.39
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: rs6563; hg19: chr9-139389184;