rs115582213

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.5854G>A(p.Val1952Met) variant causes a missense change. The variant allele was found at a frequency of 0.00957 in 1,613,920 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 92 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.89

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009421885).

BP6

Variant 19-15162524-C-T is Benign according to our data. Variant chr19-15162524-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15162524-C-T is described in Lovd as [Benign]. Variant chr19-15162524-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00813 (1238/152226) while in subpopulation AMR AF= 0.0115 (176/15286). AF 95% confidence interval is 0.0101. There are 10 homozygotes in gnomad4. There are 626 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 1238 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.5854G>A	p.Val1952Met	missense_variant	32/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.5698G>A	p.Val1900Met	missense_variant	31/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.5854G>A	p.Val1952Met	missense_variant	32/33	1	NM_000435.3	P1
NOTCH3	ENST00000597756.1 linkuse as main transcript	c.370G>A	p.Val124Met	missense_variant	3/3	2
NOTCH3	ENST00000595514.1 linkuse as main transcript	c.*62G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

1238

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00808

AC:

2032

AN:

251356

Hom.:

AF XY:

0.00823

AC XY:

1118

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.0182

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00945

GnomAD4 exome

AF:

0.00972

AC:

14202

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00950

AC XY:

6907

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00601

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.0179

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.00860

GnomAD4 genome

AF:

0.00813

AC:

1238

AN:

152226

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

626

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0188

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00902

Hom.:

Bravo

AF:

0.00715

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00847

AC:

1029

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00932

EpiControl

AF:

0.0103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NOTCH3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.18

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.60

MVP

0.75

MPC

1.4

ClinPred

0.015

GERP RS

4.5

Varity_R

0.32

gMVP

0.49

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

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