rs571831870

Positions:

• chr9-136523876-C-A
• chr9-136523876-C-G
• chr9-136523876-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_017617.5(NOTCH1):​c.244G>T​(p.Val82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. V82M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.64

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.06418729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.244G>T	p.Val82Leu	missense_variant	3/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.623+443C>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.20-4311G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.244G>T	p.Val82Leu	missense_variant	3/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2018

This sequence change replaces valine with leucine at codon 82 of the NOTCH1 protein (p.Val82Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.0010
DANN	Benign	0.55
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.19
Sift	Benign	0.64	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.027
MutPred		0.48		Loss of catalytic residue at V82 (P = 0.1143);
MVP		0.41
MPC		0.37
ClinPred		0.043	T
GERP RS		-9.3
Varity_R		0.017

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

LitVar

Other links and lift over

dbSNP: rs571831870; hg19: chr9-139418328;