rs114207045

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1PP3BP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.1490C>T(p.Ser497Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00527 in 1,593,160 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S497W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0075 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 37 hom. )

Consequence

NOTCH3
NM_000435.3 missense, splice_region

Scores

Splicing: ADA: 0.9616

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.28

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
infantile myofibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myofibromatosis, infantile, 2
Inheritance: AD Classification: LIMITED Submitted by: G2P
pulmonary arterial hypertension
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_000435.3

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 19-15188237-G-A is Benign according to our data. Variant chr19-15188237-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00746 (1136/152180) while in subpopulation AMR AF = 0.0104 (159/15286). AF 95% confidence interval is 0.00908. There are 6 homozygotes in GnomAd4. There are 584 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	Exon 9 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	Exon 9 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	Exon 9 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47
NOTCH3	ENST00000601011.1 link	c.1487C>T	p.Ser496Leu	missense_variant, splice_region_variant	Exon 9 of 23	5		ENSP00000473138.1		M0R3C9

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

1136

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00971

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00496

Gnomad OTH

AF:

0.00959

GnomAD2 exomes

AF:

0.00669

AC:

1490

AN:

222722

AF XY:

0.00670

show subpopulations

Gnomad AFR exome

AF:

0.00980

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.000466

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.00554

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00504

AC:

7256

AN:

1440980

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

3682

AN XY:

714970

show subpopulations

African (AFR)

AF:

0.00970

AC:

322

AN:

33188

American (AMR)

AF:

0.00642

AC:

272

AN:

42346

Ashkenazi Jewish (ASJ)

AF:

0.00682

AC:

175

AN:

25658

East Asian (EAS)

AF:

0.000306

AC:

AN:

39200

South Asian (SAS)

AF:

0.00625

AC:

520

AN:

83246

European-Finnish (FIN)

AF:

0.0131

AC:

679

AN:

51652

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00433

AC:

4762

AN:

1100398

Other (OTH)

AF:

0.00724

AC:

431

AN:

59546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

376

753

1129

1506

1882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152180

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

584

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00968

AC:

402

AN:

41526

American (AMR)

AF:

0.0104

AC:

159

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00871

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10604

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00496

AC:

337

AN:

67988

Other (OTH)

AF:

0.00949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00562

Hom.:

Bravo

AF:

0.00691

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00569

AC:

687

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOTCH3: BS2 -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Vascular parkinsonism;C0751587:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;na:Cerebral small vessel disease

Benign:1

Oct 01, 2024

The Egyptian Network for Neurodegenerative Diseases (ENND), The American University in Cairo

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

This rare variant (MAF 0.00738818 in 1000 Genomes / 0.007 in gnomAD) is currently classified as likely benign based on ACMG criteria. However, several studies have reported significant structural implications (PMID: 31799216) and associations with overlapping phenotypes, including CADASIL, white matter lesions (WMLs) in Parkinson’s disease (PD), and cerebral small vessel disease (CSVD) (PMIDs: 32573853, 22006983, 38790158). We observed this variant in a patient diagnosed with vascular parkinsonism—a phenotype that overlaps with CADASIL where late-onset parkinsonism has been described as one of its features. These findings warrant further investigation and may suggest that the clinical significance of this variant could require re-evaluation. The CADD score is 25.8, supporting potential deleteriousness. -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0081

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.3

L;.

PhyloP100

5.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.26

Sift

Benign

0.47

T;.

Sift4G

Benign

0.50

T;D

Polyphen

0.065

B;.

Vest4

0.31

MVP

0.99

MPC

0.42

ClinPred

0.021

GERP RS

5.0

Varity_R

0.15

gMVP

0.76

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.76

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over