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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000435.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.1490C>T	p.Ser497Leu	missense splice_region	Exon 9 of 33	NP_000426.2	Q9UM47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.1490C>T	p.Ser497Leu	missense splice_region	Exon 9 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.1490C>T	p.Ser497Leu	missense splice_region	Exon 9 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.1469C>T	p.Ser490Leu	missense splice_region	Exon 9 of 32	ENSP00000601591.1

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)

not specified (2)

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

Vascular parkinsonism;C0751587:Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy;na:Cerebral small vessel disease (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0081

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.3

PhyloP100

5.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.26

Sift

Benign

0.47

Sift4G

Benign

0.50

Polyphen

0.065

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over