chr9-136523065-C-A

Variant names:

• chr9-136523065-C-A
• rs375065108
• NM_017617.5:c.527G>T

Variant summary

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

The NM_017617.5(NOTCH1):​c.527G>T​(p.Arg176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,900 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• 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

LOC124902310 (HGNC:):

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.527G>T	p.Arg176Leu	missense_variant	Exon 4 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.20-3500G>T		intron_variant	Intron 1 of 30		XP_011517019.2
LOC124902310	XR_007061865.1	n.508-253C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.527G>T	p.Arg176Leu	missense_variant	Exon 4 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426900 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706572

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 37902

South Asian (SAS) AF: 0.00 AC: 0 AN: 81716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49568

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095144

Other (OTH) AF: 0.00 AC: 0 AN: 59016

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.11	N
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Benign	0.41	T
Sift4G	Benign	0.34	T
Polyphen		0.081	B
Vest4		0.48
MutPred		0.42		Loss of disorder (P = 0.0376);
MVP		0.82
MPC		0.53
ClinPred		0.61	D
GERP RS		1.7
Varity_R		0.47
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375065108; hg19: chr9-139417517;