rs1044009

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.6668C>T(p.Ala2223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,578,678 control chromosomes in the GnomAD database, including 454,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A2223A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.69 ( 37448 hom., cov: 33)

Exomes 𝑓: 0.76 ( 416647 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.20

Publications

76 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 (MetaRNN=9.551242E-7).

BP6

Variant 19-15160960-G-A is Benign according to our data. Variant chr19-15160960-G-A is described in ClinVar as Benign. ClinVar VariationId is 256152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.6668C>T	p.Ala2223Val	missense_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.6512C>T	p.Ala2171Val	missense_variant	Exon 32 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.6668C>T	p.Ala2223Val	missense_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

105221

AN:

152020

Hom.:

37441

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.853

Gnomad AMR

AF:

0.621

Gnomad ASJ

AF:

0.750

Gnomad EAS

AF:

0.583

Gnomad SAS

AF:

0.722

Gnomad FIN

AF:

0.815

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.785

Gnomad OTH

AF:

0.690

GnomAD2 exomes

AF:

0.714

AC:

140885

AN:

197286

AF XY:

0.723

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.767

Gnomad EAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.812

Gnomad NFE exome

AF:

0.789

Gnomad OTH exome

AF:

0.714

GnomAD4 exome

AF:

0.761

AC:

1085335

AN:

1426538

Hom.:

416647

Cov.:

AF XY:

0.761

AC XY:

537517

AN XY:

706594

show subpopulations

African (AFR)

AF:

0.514

AC:

16886

AN:

32832

American (AMR)

AF:

0.560

AC:

22158

AN:

39576

Ashkenazi Jewish (ASJ)

AF:

0.761

AC:

19198

AN:

25242

East Asian (EAS)

AF:

0.601

AC:

22915

AN:

38112

South Asian (SAS)

AF:

0.713

AC:

59535

AN:

83450

European-Finnish (FIN)

AF:

0.811

AC:

38814

AN:

47830

Middle Eastern (MID)

AF:

0.677

AC:

3848

AN:

5688

European-Non Finnish (NFE)

AF:

0.785

AC:

859252

AN:

1094844

Other (OTH)

AF:

0.725

AC:

42729

AN:

58964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

14133

28265

42398

56530

70663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20334

40668

61002

81336

101670

<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:

0.692

AC:

105253

AN:

152140

Hom.:

37448

Cov.:

AF XY:

0.691

AC XY:

51364

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.535

AC:

22199

AN:

41494

American (AMR)

AF:

0.621

AC:

9502

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

2604

AN:

3470

East Asian (EAS)

AF:

0.583

AC:

2995

AN:

5140

South Asian (SAS)

AF:

0.723

AC:

3489

AN:

4826

European-Finnish (FIN)

AF:

0.815

AC:

8644

AN:

10610

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.785

AC:

53380

AN:

67986

Other (OTH)

AF:

0.692

AC:

1461

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1600

3201

4801

6402

8002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.749

Hom.:

88506

Bravo

AF:

0.667

TwinsUK

AF:

0.776

AC:

2879

ALSPAC

AF:

0.786

AC:

3030

ESP6500AA

AF:

0.603

AC:

2506

ESP6500EA

AF:

0.801

AC:

6617

ExAC

AF:

0.694

AC:

81542

Asia WGS

AF:

0.639

AC:

2225

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

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

- -

May 18, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Apr 26, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31288479, 24086431, 28867359, 22153900, 30993645) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.66

MetaRNN

Benign

9.6e-7

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

1.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

REVEL

Benign

0.14

Sift

Benign

0.17

Sift4G

Benign

0.12

Polyphen

0.0010

Vest4

0.037

MPC

0.56

ClinPred

0.0050

GERP RS

0.43

Varity_R

0.063

gMVP

0.24

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over