rs1044006

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000435.3(NOTCH3):c.4563A>G(p.Pro1521Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 1,595,316 control chromosomes in the GnomAD database, including 637,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62274 hom., cov: 34)

Exomes 𝑓: 0.89 ( 575674 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.37

Publications

34 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 19-15174241-T-C is Benign according to our data. Variant chr19-15174241-T-C is described in ClinVar as Benign. ClinVar VariationId is 256138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

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.4563A>G	p.Pro1521Pro	synonymous	Exon 25 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.4563A>G	p.Pro1521Pro	synonymous	Exon 25 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.4698A>G	p.Pro1566Pro	synonymous	Exon 26 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.4386A>G	p.Pro1462Pro	synonymous	Exon 24 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.902

AC:

137252

AN:

152178

Hom.:

62222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.977

Gnomad AMI

AF:

0.885

Gnomad AMR

AF:

0.782

Gnomad ASJ

AF:

0.876

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.857

Gnomad FIN

AF:

0.883

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.899

Gnomad OTH

AF:

0.879

GnomAD2 exomes

AF:

0.863

AC:

185645

AN:

215228

AF XY:

0.866

show subpopulations

Gnomad AFR exome

AF:

0.980

Gnomad AMR exome

AF:

0.718

Gnomad ASJ exome

AF:

0.872

Gnomad EAS exome

AF:

0.801

Gnomad FIN exome

AF:

0.886

Gnomad NFE exome

AF:

0.900

Gnomad OTH exome

AF:

0.860

GnomAD4 exome

AF:

0.892

AC:

1287588

AN:

1443020

Hom.:

575674

Cov.:

AF XY:

0.891

AC XY:

639275

AN XY:

717490

show subpopulations

African (AFR)

AF:

0.981

AC:

32499

AN:

33118

American (AMR)

AF:

0.724

AC:

30450

AN:

42038

Ashkenazi Jewish (ASJ)

AF:

0.871

AC:

22512

AN:

25858

East Asian (EAS)

AF:

0.827

AC:

32131

AN:

38862

South Asian (SAS)

AF:

0.859

AC:

73083

AN:

85068

European-Finnish (FIN)

AF:

0.886

AC:

41663

AN:

47036

Middle Eastern (MID)

AF:

0.846

AC:

4442

AN:

5250

European-Non Finnish (NFE)

AF:

0.903

AC:

998345

AN:

1106110

Other (OTH)

AF:

0.879

AC:

52463

AN:

59680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

8111

16222

24332

32443

40554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21330

42660

63990

85320

106650

<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:

0.902

AC:

137362

AN:

152296

Hom.:

62274

Cov.:

AF XY:

0.898

AC XY:

66849

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.977

AC:

40605

AN:

41578

American (AMR)

AF:

0.782

AC:

11955

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.876

AC:

3041

AN:

3472

East Asian (EAS)

AF:

0.805

AC:

4163

AN:

5170

South Asian (SAS)

AF:

0.857

AC:

4138

AN:

4830

European-Finnish (FIN)

AF:

0.883

AC:

9380

AN:

10620

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.899

AC:

61158

AN:

68018

Other (OTH)

AF:

0.880

AC:

1857

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

699

1398

2096

2795

3494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.898

Hom.:

22666

Bravo

AF:

0.896

Asia WGS

AF:

0.854

AC:

2969

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

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

Lateral meningocele syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.15

(source)

DANN

Benign

0.67

PhyloP100

-4.4

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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