chr19-15180765-C-G

Position:

chr19-15180765-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000435.3(NOTCH3):c.3058G>C(p.Ala1020Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,602,146 control chromosomes in the GnomAD database, including 3,918 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.098 ( 1991 hom., cov: 32)

Exomes 𝑓: 0.020 ( 1927 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:10

Conservation

PhyloP100: 0.262

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 -18 ACMG points.

PM1

In a domain EGF-like 26 (size 34) in uniprot entity NOTC3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000435.3

BP4

Computational evidence support a benign effect (MetaRNN=0.005243212).

BP6

Variant 19-15180765-C-G is Benign according to our data. Variant chr19-15180765-C-G is described in ClinVar as [Benign]. Clinvar id is 9227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15180765-C-G is described in Lovd as [Benign]. Variant chr19-15180765-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 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.3058G>C	p.Ala1020Pro	missense_variant	19/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.2902G>C	p.Ala968Pro	missense_variant	18/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.3058G>C	p.Ala1020Pro	missense_variant	19/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.2899G>C	p.Ala967Pro	missense_variant	18/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes

AF:

0.0981

AC:

14929

AN:

152138

Hom.:

1982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0451

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0779

GnomAD3 exomes

AF:

0.0351

AC:

8005

AN:

228302

Hom.:

730

AF XY:

0.0310

AC XY:

3820

AN XY:

123390

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0354

Gnomad EAS exome

AF:

0.000581

Gnomad SAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.0163

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0324

GnomAD4 exome

AF:

0.0201

AC:

29164

AN:

1449890

Hom.:

1927

Cov.:

AF XY:

0.0196

AC XY:

14127

AN XY:

719994

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.0262

Gnomad4 ASJ exome

AF:

0.0349

Gnomad4 EAS exome

AF:

0.000356

Gnomad4 SAS exome

AF:

0.0283

Gnomad4 FIN exome

AF:

0.0153

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.0348

GnomAD4 genome

AF:

0.0982

AC:

14959

AN:

152256

Hom.:

1991

Cov.:

AF XY:

0.0951

AC XY:

7082

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.307

Gnomad4 AMR

AF:

0.0450

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0269

Gnomad4 FIN

AF:

0.0154

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0771

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.110

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.294

AC:

1294

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.0384

AC:

4652

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 27884173, 18765654, 19528524, 21345538, 20981092) -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 16, 2009	- -
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;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.42

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.56

T;D

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.16

Sift

Benign

0.20

T;.

Sift4G

Benign

0.30

T;T

Polyphen

0.027

B;.

Vest4

0.22

MPC

0.57

ClinPred

0.0082

GERP RS

1.4

Varity_R

0.22

gMVP

0.85

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