rs763321998

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000435.3(NOTCH3):ā€‹c.2956T>Gā€‹(p.Cys986Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

14
3
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.23
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a disulfide_bond (size 15) in uniprot entity NOTC3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000435.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 19-15180999-A-C is Pathogenic according to our data. Variant chr19-15180999-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585602.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH3NM_000435.3 linkuse as main transcriptc.2956T>G p.Cys986Gly missense_variant 18/33 ENST00000263388.7 NP_000426.2 Q9UM47
NOTCH3XM_005259924.5 linkuse as main transcriptc.2800T>G p.Cys934Gly missense_variant 17/32 XP_005259981.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH3ENST00000263388.7 linkuse as main transcriptc.2956T>G p.Cys986Gly missense_variant 18/331 NM_000435.3 ENSP00000263388.1 Q9UM47
NOTCH3ENST00000601011.1 linkuse as main transcriptc.2797T>G p.Cys933Gly missense_variant 17/235 ENSP00000473138.1 M0R3C9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.92e-7
AC:
1
AN:
1445222
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
717690
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000258
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
ExAC
AF:
0.00000829
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMar 02, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.88
D;T
Eigen
Pathogenic
0.81
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.70
T;T
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
1.0
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-10
D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.99
MutPred
1.0
Loss of stability (P = 0.0526);.;
MVP
1.0
MPC
1.4
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.91
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763321998; hg19: chr19-15291810; API