rs587778559

Positions:

• chr9-136513479-CATT-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_017617.5(NOTCH1):​c.2263_2265del​(p.Asn755del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,244 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N755N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: NOTCH1 NM_017617.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:2
• Conservation: PhyloP100: 7.58

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_017617.5. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.2263_2265del	p.Asn755del	inframe_deletion	14/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.507+3501_507+3503del		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.1540_1542del	p.Asn514del	inframe_deletion	11/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.2263_2265del	p.Asn755del	inframe_deletion	14/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000218 AC: 54 AN: 248262 Hom.: 0 AF XY: 0.000289 AC XY: 39 AN XY: 135144

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1460884 Hom.: 2 AF XY: 0.000330 AC XY: 240 AN XY: 726728

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000377

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74504

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000230

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2017	The c.2263_2265delAAT (p.N755del) alteration is located in exon 14 (coding exon 14) of the NOTCH1 gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.2263 and c.2265, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2024	Has not been previously published as pathogenic or benign in association with a NOTCH1-related disorder to our knowledge; In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34057693) -

Adams-Oliver syndrome 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This variant, c.2263_2265del, results in the deletion of 1 amino acid(s) of the NOTCH1 protein (p.Asn755del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587778559, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 134914). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aortic valve disease 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Adams-Oliver syndrome;CN236429:Congenital heart anomalies Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant classified as Uncertain significance and reported on 08-05-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

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: rs587778559; hg19: chr9-139407931;