rs2074619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000435.3(NOTCH3):c.5363-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,611,540 control chromosomes in the GnomAD database, including 643,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 61879 hom., cov: 32)

Exomes 𝑓: 0.89 ( 581534 hom. )

Consequence

NOTCH3
NM_000435.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0440

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-15166108-G-A is Benign according to our data. Variant chr19-15166108-G-A is described in ClinVar as Benign. ClinVar VariationId is 256141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.5363-17C>T		intron_variant	Intron 29 of 32	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.5207-17C>T		intron_variant	Intron 28 of 31		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOTCH3	ENST00000263388.7 link	c.5363-17C>T	intron_variant	Intron 29 of 32	1	NM_000435.3	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000595514.1 link	n.227-593C>T	intron_variant	Intron 2 of 4	3		ENSP00000470661.1	M0QZN3
NOTCH3	ENST00000597756.1 link	c.-142C>T	upstream_gene_variant		2		ENSP00000468879.1	M0QX38

Frequencies

GnomAD3 genomes

AF:

0.900

AC:

136740

AN:

151956

Hom.:

61832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.971

Gnomad AMI

AF:

0.885

Gnomad AMR

AF:

0.781

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.846

Gnomad FIN

AF:

0.883

Gnomad MID

AF:

0.883

Gnomad NFE

AF:

0.899

Gnomad OTH

AF:

0.876

GnomAD2 exomes

AF:

0.862

AC:

214886

AN:

249362

AF XY:

0.864

show subpopulations

Gnomad AFR exome

AF:

0.973

Gnomad AMR exome

AF:

0.712

Gnomad ASJ exome

AF:

0.872

Gnomad EAS exome

AF:

0.797

Gnomad FIN exome

AF:

0.886

Gnomad NFE exome

AF:

0.900

Gnomad OTH exome

AF:

0.861

GnomAD4 exome

AF:

0.892

AC:

1301240

AN:

1459466

Hom.:

581534

Cov.:

AF XY:

0.890

AC XY:

646445

AN XY:

726244

show subpopulations

African (AFR)

AF:

0.975

AC:

32632

AN:

33452

American (AMR)

AF:

0.721

AC:

32236

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

22780

AN:

26130

East Asian (EAS)

AF:

0.826

AC:

32781

AN:

39686

South Asian (SAS)

AF:

0.849

AC:

73221

AN:

86194

European-Finnish (FIN)

AF:

0.887

AC:

47320

AN:

53352

Middle Eastern (MID)

AF:

0.847

AC:

4874

AN:

5754

European-Non Finnish (NFE)

AF:

0.903

AC:

1002440

AN:

1109910

Other (OTH)

AF:

0.878

AC:

52956

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

6802

13604

20407

27209

34011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21374

42748

64122

85496

106870

<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:

0.900

AC:

136845

AN:

152074

Hom.:

61879

Cov.:

AF XY:

0.895

AC XY:

66550

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.971

AC:

40312

AN:

41530

American (AMR)

AF:

0.781

AC:

11925

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

3045

AN:

3470

East Asian (EAS)

AF:

0.805

AC:

4142

AN:

5144

South Asian (SAS)

AF:

0.846

AC:

4079

AN:

4822

European-Finnish (FIN)

AF:

0.883

AC:

9329

AN:

10564

Middle Eastern (MID)

AF:

0.874

AC:

257

AN:

294

European-Non Finnish (NFE)

AF:

0.899

AC:

61100

AN:

67958

Other (OTH)

AF:

0.877

AC:

1851

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

680

1360

2041

2721

3401

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:

0.892

Hom.:

11157

Bravo

AF:

0.894

Asia WGS

AF:

0.843

AC:

2932

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lateral meningocele syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.90

(source)

DANN

Benign

0.23

PhyloP100

0.044

PromoterAI

-0.053

Neutral

(source)

Mutation Taster

=100/0

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

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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