rs1043996

Positions:

chr19-15184323-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000435.3(NOTCH3):c.2538C>T(p.Cys846=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15184323-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.2538C>T	p.Cys846=	synonymous_variant	16/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.2410+583C>T		intron_variant			XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.2538C>T	p.Cys846=	synonymous_variant	16/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.2407+583C>T		intron_variant		5		ENSP00000473138

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

GnomAD3 exomes

AF:

0.641

AC:

160953

AN:

251120

Hom.:

53670

AF XY:

0.653

AC XY:

88659

AN XY:

135800

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 SAS exome

AF:

0.648

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

Gnomad4 AFR exome

AF:

0.244

Gnomad4 AMR exome

AF:

0.510

Gnomad4 ASJ exome

AF:

0.676

Gnomad4 EAS exome

AF:

0.613

Gnomad4 SAS exome

AF:

0.646

Gnomad4 FIN exome

AF:

0.758

Gnomad4 NFE exome

AF:

0.721

Gnomad4 OTH exome

AF:

0.657

GnomAD4 genome

AF:

0.572

AC:

86891

AN:

152016

Hom.:

27881

Cov.:

AF XY:

0.574

AC XY:

42671

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.556

Gnomad4 ASJ

AF:

0.669

Gnomad4 EAS

AF:

0.599

Gnomad4 SAS

AF:

0.663

Gnomad4 FIN

AF:

0.761

Gnomad4 NFE

AF:

0.718

Gnomad4 OTH

AF:

0.595

Alfa

AF:

0.680

Hom.:

57003

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	- -

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

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect - CureCADASIL	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.1

DANN

Benign

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over