rs3124596

Variant names:

• chr9-136507052-G-A
• rs3124596
• NM_017617.5:c.3644-79C>T

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.3644-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,555,742 control chromosomes in the GnomAD database, including 219,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25862 hom., cov: 36)
  • Exomes 𝑓: 0.52 (193943 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.05
• Publications: 20 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-136507052-G-A is Benign according to our data. Variant chr9-136507052-G-A is described in ClinVar as [Benign]. Clinvar id is 678563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.3644-79C>T		intron_variant	Intron 22 of 33	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.2921-79C>T		intron_variant	Intron 19 of 30		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.3644-79C>T		intron_variant	Intron 22 of 33		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87215 AN: 152098 Hom.: 25836 Cov.: 36

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.561

GnomAD4 exome AF: 0.519 AC: 729078 AN: 1403524 Hom.: 193943 AF XY: 0.523 AC XY: 363343 AN XY: 694184

African (AFR) AF: 0.674 AC: 21417 AN: 31780

American (AMR) AF: 0.661 AC: 24672 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15363 AN: 25272

East Asian (EAS) AF: 0.837 AC: 30422 AN: 36338

South Asian (SAS) AF: 0.638 AC: 51271 AN: 80358

European-Finnish (FIN) AF: 0.457 AC: 22270 AN: 48718

Middle Eastern (MID) AF: 0.583 AC: 2378 AN: 4076

European-Non Finnish (NFE) AF: 0.489 AC: 529153 AN: 1081580

Other (OTH) AF: 0.553 AC: 32132 AN: 58084

GnomAD4 genome AF: 0.573 AC: 87296 AN: 152218 Hom.: 25862 Cov.: 36 AF XY: 0.579 AC XY: 43077 AN XY: 74428

African (AFR) AF: 0.674 AC: 28003 AN: 41542

American (AMR) AF: 0.601 AC: 9203 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2136 AN: 3472

East Asian (EAS) AF: 0.881 AC: 4547 AN: 5162

South Asian (SAS) AF: 0.636 AC: 3073 AN: 4832

European-Finnish (FIN) AF: 0.454 AC: 4814 AN: 10602

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33831 AN: 67984

Other (OTH) AF: 0.564 AC: 1193 AN: 2116

Alfa AF: 0.522 Hom.: 41365

Bravo AF: 0.591

Asia WGS AF: 0.756 AC: 2627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.71
DANN	Benign	0.60
PhyloP100		-3.0
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: rs3124596; hg19: chr9-139401504; COSMIC: COSV53098415; COSMIC: COSV53098415;