rs114447350

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.6221C>T(p.Pro2074Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00476 in 1,525,304 control chromosomes in the GnomAD database, including 287 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 (★★).

Frequency

Genomes: 𝑓 0.025 ( 148 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 139 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.61

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=0.001966834).

BP6

Variant 19-15161407-G-A is Benign according to our data. Variant chr19-15161407-G-A is described in ClinVar as [Benign]. Clinvar id is 256150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15161407-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 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.6221C>T	p.Pro2074Leu	missense_variant	33/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.6065C>T	p.Pro2022Leu	missense_variant	32/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.6221C>T	p.Pro2074Leu	missense_variant	33/33	1	NM_000435.3	ENSP00000263388	P1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3761

AN:

152082

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0866

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.00563

AC:

702

AN:

124650

Hom.:

AF XY:

0.00415

AC XY:

283

AN XY:

68138

show subpopulations

Gnomad AFR exome

AF:

0.0935

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000984

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000376

Gnomad OTH exome

AF:

0.00385

GnomAD4 exome

AF:

0.00254

AC:

3485

AN:

1373104

Hom.:

139

Cov.:

AF XY:

0.00221

AC XY:

1491

AN XY:

675262

show subpopulations

Gnomad4 AFR exome

AF:

0.0918

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000282

Gnomad4 SAS exome

AF:

0.000142

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.00569

GnomAD4 genome

AF:

0.0248

AC:

3778

AN:

152200

Hom.:

148

Cov.:

AF XY:

0.0238

AC XY:

1773

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0868

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00745

Hom.:

Bravo

AF:

0.0289

ESP6500AA

AF:

0.0483

AC:

128

ESP6500EA

AF:

0.000332

AC:

ExAC

AF:

0.00251

AC:

240

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2021	- -

Pulmonary arterial hypertension

Benign:1

Benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

REVEL

Benign

0.15

Sift

Benign

0.17

Sift4G

Benign

0.28

Polyphen

0.051

Vest4

0.15

MVP

0.90

MPC

0.57

ClinPred

0.0081

GERP RS

3.8

Varity_R

0.086

gMVP

0.55

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