9-136501021-C-T

Variant names:

• chr9-136501021-C-T
• rs3124999
• NM_017617.5:c.5639-174G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017617.5(NOTCH1):​c.5639-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,102 control chromosomes in the GnomAD database, including 15,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (15465 hom., cov: 33)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.716
• Publications: 14 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: Orphanet, Illumina
• Adams-Oliver syndrome 5

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

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

  Inheritance: AD Classification: STRONG Submitted by: G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136501021-C-T is Benign according to our data. Variant chr9-136501021-C-T is described in ClinVar as Benign. ClinVar VariationId is 677905.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 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.5639-174G>A		intron	N/A	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.5639-174G>A		intron	N/A	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.5528-174G>A		intron	N/A	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.5525-174G>A		intron	N/A	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66430 AN: 151982 Hom.: 15448 Cov.: 33

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.437 AC: 66484 AN: 152102 Hom.: 15465 Cov.: 33 AF XY: 0.443 AC XY: 32918 AN XY: 74358

African (AFR) AF: 0.511 AC: 21206 AN: 41460

American (AMR) AF: 0.483 AC: 7379 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1150 AN: 3470

East Asian (EAS) AF: 0.880 AC: 4555 AN: 5176

South Asian (SAS) AF: 0.383 AC: 1846 AN: 4824

European-Finnish (FIN) AF: 0.394 AC: 4168 AN: 10588

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

European-Non Finnish (NFE) AF: 0.367 AC: 24962 AN: 67978

Other (OTH) AF: 0.422 AC: 894 AN: 2116

Alfa AF: 0.391 Hom.: 20949

Bravo AF: 0.451

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.62
PhyloP100		-0.72
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: rs3124999; hg19: chr9-139395473; COSMIC: COSV53098650;