rs1043994

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.606A>G(p.Ala202Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,208 control chromosomes in the GnomAD database, including 615,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57799 hom., cov: 34)

Exomes 𝑓: 0.87 ( 558124 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.47

Publications

48 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=-0.89).

BP6

Variant 19-15192033-T-C is Benign according to our data. Variant chr19-15192033-T-C is described in ClinVar as Benign. ClinVar VariationId is 256148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 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.606A>G	p.Ala202Ala	synonymous	Exon 4 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.606A>G	p.Ala202Ala	synonymous	Exon 4 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.606A>G	p.Ala202Ala	synonymous	Exon 4 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.585A>G	p.Ala195Ala	synonymous	Exon 4 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.870

AC:

132353

AN:

152104

Hom.:

57761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.866

Gnomad AMR

AF:

0.763

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.865

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.863

Gnomad MID

AF:

0.861

Gnomad NFE

AF:

0.876

Gnomad OTH

AF:

0.847

GnomAD2 exomes

AF:

0.848

AC:

212142

AN:

250060

AF XY:

0.851

show subpopulations

Gnomad AFR exome

AF:

0.909

Gnomad AMR exome

AF:

0.701

Gnomad ASJ exome

AF:

0.871

Gnomad EAS exome

AF:

0.863

Gnomad FIN exome

AF:

0.866

Gnomad NFE exome

AF:

0.879

Gnomad OTH exome

AF:

0.845

GnomAD4 exome

AF:

0.873

AC:

1275651

AN:

1460986

Hom.:

558124

Cov.:

AF XY:

0.872

AC XY:

633809

AN XY:

726822

show subpopulations

African (AFR)

AF:

0.908

AC:

30391

AN:

33480

American (AMR)

AF:

0.708

AC:

31627

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

22784

AN:

26136

East Asian (EAS)

AF:

0.880

AC:

34938

AN:

39696

South Asian (SAS)

AF:

0.841

AC:

72501

AN:

86256

European-Finnish (FIN)

AF:

0.866

AC:

45521

AN:

52558

Middle Eastern (MID)

AF:

0.825

AC:

4761

AN:

5768

European-Non Finnish (NFE)

AF:

0.882

AC:

981180

AN:

1112004

Other (OTH)

AF:

0.860

AC:

51948

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

11522

23044

34567

46089

57611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21340

42680

64020

85360

106700

<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:

0.870

AC:

132443

AN:

152222

Hom.:

57799

Cov.:

AF XY:

0.867

AC XY:

64511

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.907

AC:

37674

AN:

41548

American (AMR)

AF:

0.763

AC:

11665

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

3045

AN:

3470

East Asian (EAS)

AF:

0.866

AC:

4462

AN:

5154

South Asian (SAS)

AF:

0.834

AC:

4021

AN:

4822

European-Finnish (FIN)

AF:

0.863

AC:

9153

AN:

10608

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.876

AC:

59601

AN:

68016

Other (OTH)

AF:

0.844

AC:

1783

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

916

1832

2749

3665

4581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.879

Hom.:

32884

Bravo

AF:

0.865

Asia WGS

AF:

0.837

AC:

2908

AN:

3478

EpiCase

AF:

0.872

EpiControl

AF:

0.867

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (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

-0.89

CADD

Benign

0.10

(source)

DANN

Benign

0.18

PhyloP100

-3.5

Mutation Taster

=98/2

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