9-136504703-C-A

Variant names:

• chr9-136504703-C-A
• rs749490844
• NM_017617.5:c.4988G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017617.5(NOTCH1):​c.4988G>T​(p.Arg1663Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,382,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1663Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.4988G>T	p.Arg1663Leu	missense_variant	Exon 26 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.4265G>T	p.Arg1422Leu	missense_variant	Exon 23 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.4988G>T	p.Arg1663Leu	missense_variant	Exon 26 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1382360 Hom.: 0 Cov.: 33 AF XY: 0.00000294 AC XY: 2 AN XY: 680014

African (AFR) AF: 0.00 AC: 0 AN: 31208

American (AMR) AF: 0.00 AC: 0 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24226

East Asian (EAS) AF: 0.00 AC: 0 AN: 35532

South Asian (SAS) AF: 0.00 AC: 0 AN: 77394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4438

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1071092

Other (OTH) AF: 0.00 AC: 0 AN: 57160

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:1

Jun 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 2012405). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1663 of the NOTCH1 protein (p.Arg1663Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.034
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.014	D
Polyphen		0.69	P
Vest4		0.43
MutPred		0.41		Gain of sheet (P = 0.0266);
MVP		0.82
MPC		1.5
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.37
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749490844; hg19: chr9-139399155;