9-136544096-C-G

Variant names:

• chr9-136544096-C-G
• rs869025260
• NM_017617.5:c.68G>C

Variant summary

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

The NM_017617.5(NOTCH1):​c.68G>C​(p.Arg23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,936 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. R23L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.96
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.68G>C	p.Arg23Pro	missense	Exon 2 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.68G>C	p.Arg23Pro	missense	Exon 2 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.68G>C	p.Arg23Pro	missense	Exon 2 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.68G>C	p.Arg23Pro	missense	Exon 2 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000538 AC: 1 AN: 185998 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703780

African (AFR) AF: 0.00 AC: 0 AN: 32648

American (AMR) AF: 0.00 AC: 0 AN: 39236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 37742

South Asian (SAS) AF: 0.00 AC: 0 AN: 81086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4198

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093064

Other (OTH) AF: 0.00 AC: 0 AN: 58816

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Adams-Oliver syndrome 5 (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.47
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.97	D
Vest4		0.76
MutPred		0.38		Gain of catalytic residue at P22 (P = 0.0186)
MVP		0.92
MPC		0.93
ClinPred		0.65	D
GERP RS		2.7
Varity_R		0.31
Mutation Taster		=61/39	polymorphism

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: rs869025260; hg19: chr9-139438548;