rs78501403

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.4679G>C(p.Arg1560Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000893 in 1,604,112 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1560Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 2 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.90

Publications

9 publications found

Variant links:

COSMIC-nc: COSV54635596

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 Gene-Disease associations (from GenCC):

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
infantile myofibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myofibromatosis, infantile, 2
Inheritance: AD Classification: LIMITED Submitted by: G2P
pulmonary arterial hypertension
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009254307).

BP6

Variant 19-15174125-C-G is Benign according to our data. Variant chr19-15174125-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (704/152368) while in subpopulation AFR AF = 0.016 (666/41586). AF 95% confidence interval is 0.015. There are 7 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.4679G>C	p.Arg1560Pro	missense_variant	Exon 25 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.4523G>C	p.Arg1508Pro	missense_variant	Exon 24 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.4679G>C	p.Arg1560Pro	missense_variant	Exon 25 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

699

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00115

AC:

279

AN:

242438

AF XY:

0.000853

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.000728

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000562

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000923

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000501

AC:

728

AN:

1451744

Hom.:

Cov.:

AF XY:

0.000429

AC XY:

309

AN XY:

720518

show subpopulations

African (AFR)

AF:

0.0176

AC:

583

AN:

33208

American (AMR)

AF:

0.000832

AC:

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39474

South Asian (SAS)

AF:

0.0000465

AC:

AN:

85984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51918

Middle Eastern (MID)

AF:

0.00187

AC:

AN:

4814

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1106074

Other (OTH)

AF:

0.00125

AC:

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00462

AC:

704

AN:

152368

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

326

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.0160

AC:

666

AN:

41586

American (AMR)

AF:

0.00183

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000273

Hom.:

Bravo

AF:

0.00535

ESP6500AA

AF:

0.0103

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00139

AC:

169

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24086431) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.21

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

0.97

PhyloP100

4.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.61

Sift

Benign

0.24

Sift4G

Benign

0.22

Polyphen

0.99

Vest4

0.67

MVP

1.0

MPC

1.8

ClinPred

0.018

GERP RS

4.5

Varity_R

0.89

gMVP

0.99

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over