9-136494732-A-G

Variant names:

• chr9-136494732-A-G
• rs6563
• NM_017617.5:c.*1339T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.585
• Publications: 33 publications found

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]

NOTCH1 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• NOTCH1-related AOS spectrum disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leukodystrophy

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1288748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017617.5. 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
	NOTCH1	NM_017617.5	MANE Select	c.*1339T>C		3_prime_UTR	Exon 34 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.*1339T>C		3_prime_UTR	Exon 34 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.*1339T>C		3_prime_UTR	Exon 34 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.*1339T>C		3_prime_UTR	Exon 33 of 33	ENSP00000505319.1	A0A7P0T8U6

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

African (AFR) AF: 0.564 AC: 4045 AN: 7176

American (AMR) AF: 0.445 AC: 3304 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 4240 AN: 9232

East Asian (EAS) AF: 0.773 AC: 17796 AN: 23028

South Asian (SAS) AF: 0.278 AC: 843 AN: 3032

European-Finnish (FIN) AF: 0.557 AC: 11606 AN: 20830

Middle Eastern (MID) AF: 0.366 AC: 474 AN: 1294

European-Non Finnish (NFE) AF: 0.485 AC: 76669 AN: 157974

Other (OTH) AF: 0.496 AC: 8116 AN: 16362

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

African (AFR) AF: 0.561 AC: 23276 AN: 41502

American (AMR) AF: 0.464 AC: 7083 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3470

East Asian (EAS) AF: 0.724 AC: 3738 AN: 5160

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4828

European-Finnish (FIN) AF: 0.563 AC: 5957 AN: 10590

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32975 AN: 67964

Other (OTH) AF: 0.498 AC: 1052 AN: 2114

Alfa AF: 0.482 Hom.: 19182

Bravo AF: 0.509

Asia WGS AF: 0.458 AC: 1594 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.39
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs6563; hg19: chr9-139389184;