rs760472019

chr19-15181723-G-Achr19-15181723-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000435.3(NOTCH3):c.2645C>T(p.Pro882Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P882R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.2645C>T	p.Pro882Leu	missense_variant	17/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.2489C>T	p.Pro830Leu	missense_variant	16/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.2645C>T	p.Pro882Leu	missense_variant	17/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.2486C>T	p.Pro829Leu	missense_variant	16/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419332 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 701996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2022

This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 1057230). This variant has not been reported in the literature in individuals affected with NOTCH3-related conditions. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 882 of the NOTCH3 protein (p.Pro882Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.095	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.33
Sift	Benign	0.27	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.45	B;.
Vest4		0.20
MutPred		0.55		Loss of disorder (P = 0.1157);.;
MVP		0.94
MPC		1.0
ClinPred		0.51	D
GERP RS		4.4
Varity_R		0.11
gMVP		0.41

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: rs760472019; hg19: chr19-15292534;