rs1043996

Variant names:

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.2538C>T(p.Cys846Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,613,270 control chromosomes in the GnomAD database, including 385,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 27881 hom., cov: 31)

Exomes 𝑓: 0.69 ( 357370 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.347

Publications

35 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 19-15184323-G-A is Benign according to our data. Variant chr19-15184323-G-A is described in ClinVar as Benign. ClinVar VariationId is 256129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.347 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.2538C>T	p.Cys846Cys	synonymous_variant	Exon 16 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.2410+583C>T		intron_variant	Intron 15 of 31		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.2538C>T	p.Cys846Cys	synonymous_variant	Exon 16 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47
NOTCH3	ENST00000601011.1 link	c.2407+583C>T		intron_variant	Intron 15 of 22	5		ENSP00000473138.1		M0R3C9

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86879

AN:

151898

Hom.:

27883

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.627

Gnomad AMR

AF:

0.556

Gnomad ASJ

AF:

0.669

Gnomad EAS

AF:

0.598

Gnomad SAS

AF:

0.662

Gnomad FIN

AF:

0.761

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.718

Gnomad OTH

AF:

0.595

GnomAD2 exomes

AF:

0.641

AC:

160953

AN:

251120

AF XY:

0.653

show subpopulations

Gnomad AFR exome

AF:

0.256

Gnomad AMR exome

AF:

0.504

Gnomad ASJ exome

AF:

0.675

Gnomad EAS exome

AF:

0.606

Gnomad FIN exome

AF:

0.756

Gnomad NFE exome

AF:

0.716

Gnomad OTH exome

AF:

0.653

GnomAD4 exome

AF:

0.694

AC:

1013564

AN:

1461254

Hom.:

357370

Cov.:

AF XY:

0.694

AC XY:

504333

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.244

AC:

8161

AN:

33470

American (AMR)

AF:

0.510

AC:

22799

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

17654

AN:

26134

East Asian (EAS)

AF:

0.613

AC:

24332

AN:

39690

South Asian (SAS)

AF:

0.646

AC:

55747

AN:

86244

European-Finnish (FIN)

AF:

0.758

AC:

40380

AN:

53292

Middle Eastern (MID)

AF:

0.612

AC:

3525

AN:

5764

European-Non Finnish (NFE)

AF:

0.721

AC:

801274

AN:

1111584

Other (OTH)

AF:

0.657

AC:

39692

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

16323

32646

48969

65292

81615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19744

39488

59232

78976

98720

<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:

0.572

AC:

86891

AN:

152016

Hom.:

27881

Cov.:

AF XY:

0.574

AC XY:

42671

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.263

AC:

10916

AN:

41460

American (AMR)

AF:

0.556

AC:

8494

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.669

AC:

2322

AN:

3472

East Asian (EAS)

AF:

0.599

AC:

3083

AN:

5150

South Asian (SAS)

AF:

0.663

AC:

3188

AN:

4810

European-Finnish (FIN)

AF:

0.761

AC:

8039

AN:

10558

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.718

AC:

48844

AN:

67986

Other (OTH)

AF:

0.595

AC:

1253

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1641

3282

4924

6565

8206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<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:

0.671

Hom.:

115940

Bravo

AF:

0.541

Asia WGS

AF:

0.602

AC:

2091

AN:

3478

EpiCase

AF:

0.705

EpiControl

AF:

0.698

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:3Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect - CureCADASIL

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 06-21-2005 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

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

-0.56

CADD

Benign

6.1

(source)

DANN

Benign

0.38

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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