19-15162570-A-G

Variant names:

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.5816-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 1,612,158 control chromosomes in the GnomAD database, including 644,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62118 hom., cov: 31)

Exomes 𝑓: 0.89 ( 582047 hom. )

Consequence

NOTCH3
NM_000435.3 splice_region, intron

Scores

Splicing: ADA: 0.000005957

Clinical Significance

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

Conservation

PhyloP100: 0.364

Publications

18 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=-0.88).

BP6

Variant 19-15162570-A-G is Benign according to our data. Variant chr19-15162570-A-G is described in ClinVar as Benign. ClinVar VariationId is 256145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.5816-8T>C		splice_region_variant, intron_variant	Intron 31 of 32	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 link	c.5660-8T>C		splice_region_variant, intron_variant	Intron 30 of 31		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
NOTCH3	ENST00000263388.7 link	c.5816-8T>C	splice_region_variant, intron_variant	Intron 31 of 32	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000597756.1 link	c.329-8T>C	splice_region_variant, intron_variant	Intron 2 of 2	2		ENSP00000468879.1
NOTCH3	ENST00000595514.1 link	n.*24-8T>C	splice_region_variant, intron_variant	Intron 3 of 4	3		ENSP00000470661.1

Frequencies

GnomAD3 genomes

AF:

0.901

AC:

137041

AN:

152068

Hom.:

62067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.974

Gnomad AMI

AF:

0.885

Gnomad AMR

AF:

0.781

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.852

Gnomad FIN

AF:

0.884

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.899

Gnomad OTH

AF:

0.878

GnomAD2 exomes

AF:

0.864

AC:

216238

AN:

250336

AF XY:

0.866

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.872

Gnomad EAS exome

AF:

0.800

Gnomad FIN exome

AF:

0.887

Gnomad NFE exome

AF:

0.900

Gnomad OTH exome

AF:

0.862

GnomAD4 exome

AF:

0.892

AC:

1302111

AN:

1459972

Hom.:

582047

Cov.:

AF XY:

0.891

AC XY:

646816

AN XY:

726344

show subpopulations

African (AFR)

AF:

0.979

AC:

32739

AN:

33444

American (AMR)

AF:

0.722

AC:

32186

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

22774

AN:

26124

East Asian (EAS)

AF:

0.827

AC:

32812

AN:

39690

South Asian (SAS)

AF:

0.853

AC:

73505

AN:

86152

European-Finnish (FIN)

AF:

0.887

AC:

47200

AN:

53204

Middle Eastern (MID)

AF:

0.847

AC:

4869

AN:

5748

European-Non Finnish (NFE)

AF:

0.903

AC:

1003011

AN:

1110702

Other (OTH)

AF:

0.879

AC:

53015

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

6535

13070

19604

26139

32674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21396

42792

64188

85584

106980

<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:

0.901

AC:

137150

AN:

152186

Hom.:

62118

Cov.:

AF XY:

0.897

AC XY:

66714

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.974

AC:

40475

AN:

41542

American (AMR)

AF:

0.781

AC:

11928

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

3047

AN:

3472

East Asian (EAS)

AF:

0.806

AC:

4148

AN:

5148

South Asian (SAS)

AF:

0.851

AC:

4111

AN:

4828

European-Finnish (FIN)

AF:

0.884

AC:

9357

AN:

10590

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.899

AC:

61161

AN:

68014

Other (OTH)

AF:

0.879

AC:

1858

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

661

1322

1983

2644

3305

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:

0.905

Hom.:

26237

Bravo

AF:

0.895

Asia WGS

AF:

0.850

AC:

2956

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2019

GeneDx

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

- -

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 12, 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

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.3

(source)

DANN

Benign

0.59

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000060

dbscSNV1_RF

Benign

0.0

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