chr9-136517316-C-A

Position:

• chr9-136517316-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017617.5(NOTCH1):​c.1511G>T​(p.Arg504Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.515

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.1511G>T	p.Arg504Leu	missense_variant	9/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.508-6002C>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.788G>T	p.Arg263Leu	missense_variant	6/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.1511G>T	p.Arg504Leu	missense_variant	9/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.080	N
MutationTaster	Benign	0.83	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.72	T
Sift4G	Benign	0.30	T
Polyphen		0.0080	B
Vest4		0.43
MutPred		0.65		Gain of methylation at K508 (P = 0.1756);
MVP		0.72
MPC		0.55
ClinPred		0.60	D
GERP RS		2.3
Varity_R		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139411768;