rs1044009

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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

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=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 id is 256152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15160960-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.6668C>T	p.Ala2223Val	missense_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.6512C>T	p.Ala2171Val	missense_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.6668C>T	p.Ala2223Val	missense_variant	33/33	1	NM_000435.3	P1

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

GnomAD3 exomes

AF:

0.714

AC:

140885

AN:

197286

Hom.:

51311

AF XY:

0.723

AC XY:

78372

AN XY:

108336

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 SAS exome

AF:

0.716

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

Gnomad4 AFR exome

AF:

0.514

Gnomad4 AMR exome

AF:

0.560

Gnomad4 ASJ exome

AF:

0.761

Gnomad4 EAS exome

AF:

0.601

Gnomad4 SAS exome

AF:

0.713

Gnomad4 FIN exome

AF:

0.811

Gnomad4 NFE exome

AF:

0.785

Gnomad4 OTH exome

AF:

0.725

GnomAD4 genome

AF:

0.692

AC:

105253

AN:

152140

Hom.:

37448

Cov.:

AF XY:

0.691

AC XY:

51364

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.535

Gnomad4 AMR

AF:

0.621

Gnomad4 ASJ

AF:

0.750

Gnomad4 EAS

AF:

0.583

Gnomad4 SAS

AF:

0.723

Gnomad4 FIN

AF:

0.815

Gnomad4 NFE

AF:

0.785

Gnomad4 OTH

AF:

0.692

Alfa

AF:

0.759

Hom.:

67913

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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	Eurofins Ntd Llc (ga)	May 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 31288479, 24086431, 28867359, 22153900, 30993645) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.5

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

MutationTaster

Benign

1.0

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

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