rs864622062

Variant names:

• chr9-136502438-C-A
• rs864622062
• NM_017617.5:c.5218G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136502438-C-A
• chr9-136502438-C-G
• chr9-136502438-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017617.5(NOTCH1):​c.5218G>T​(p.Ala1740Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3084271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.5218G>T	p.Ala1740Ser	missense_variant	Exon 28 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.4495G>T	p.Ala1499Ser	missense_variant	Exon 25 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5218G>T	p.Ala1740Ser	missense_variant	Exon 28 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2014

Molecular and Medical Genetics Group, King's College London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 01, 2017

Centre of Medical Genetics, University of Antwerp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aortic valve disease 1 Uncertain:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.73	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Uncertain	0.027	D
Sift4G	Benign	0.35	T
Polyphen		0.13	B
Vest4		0.21
MutPred		0.50		Gain of loop (P = 0.0045);
MVP		0.76
MPC		0.73
ClinPred		0.45	T
GERP RS		3.7
Varity_R		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs864622062; hg19: chr9-139396890;