rs142031490

chr19-15197564-C-Gchr19-15197564-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000435.3(NOTCH3):c.133G>C(p.Asp45His) variant causes a missense change. The variant allele was found at a frequency of 0.00000993 in 1,611,474 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D45D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 3.67

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]

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000435.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.133G>C	p.Asp45His	missense_variant	2/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.133G>C	p.Asp45His	missense_variant	2/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.133G>C	p.Asp45His	missense_variant	2/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.130G>C	p.Asp44His	missense_variant	2/23	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000818

AC:

AN:

244642

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459512

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

725994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 08, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. This variant is statistically more frequent in the patient population than in the general population, which is weak evidence this variant may be disease causing. This variant has been identified in cis with NOTCH3 c.154G>A in published literature, general population data, and our internal patient data (PMID: 31836585, The Genome Aggregation Database (gnomAD), Athena Diagnostics internal data). Computational tools disagree on the variant's effect on normal protein function. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 29, 2022	BP1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 45 of the NOTCH3 protein (p.Asp45His). This variant is present in population databases (rs142031490, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of NOTCH3-related conditions (PMID: 31836585, 31915071). ClinVar contains an entry for this variant (Variation ID: 447782). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. 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. -

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 02, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect - CureCADASIL	-	Variant interpreted as Uncertain significance and reported on 10-23-2020 by lab or GTR ID London Health Sciences Centre/St. Joseph's Health Care London, Pathology and Laboratory Medicine. GenomeConnect - CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 07, 2019

The NOTCH3 c.133G>C; p.Asp45His variant (rs142031490) is reported in the literature in cis to a p.Gly52Arg missense variant in individual affected with cerebral small vessel disease with a family history of stroke and migraines (Tan 2018). The p.Asp45His variant is reported in ClinVar (Variation ID: 447782), and it is found on only two chromosomes (2/244642 alleles) in the Genome Aggregation Database. The aspartate at codon 45 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Structural modeling suggests this variant may perturb the secondary structure of EGF domain 1 and influence the orientation of a cysteine residue involved in a critical disulfide bond, though further studies would be required to determine a functional effect (Tan 2018). Given the lack of clinical and functional data, the significance of the p.Asp45His variant is uncertain at this time. References: Tan, YYR. Genetics of Cerebral Small Vessel Disease (Doctoral thesis). 2018. https://doi.org/10.17863/CAM.30570 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.6

D;.

REVEL

Pathogenic

0.72

Sift

Benign

0.045

D;.

Sift4G

Benign

0.17

T;T

Polyphen

0.25

B;.

Vest4

0.71

MVP

1.0

MPC

1.3

ClinPred

0.87

GERP RS

3.9

Varity_R

0.25

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over