rs35793356

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000435.3(NOTCH3):c.1782C>T(p.Gly594Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,614,124 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 32 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.69

Publications

4 publications found

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 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 19-15187163-G-A is Benign according to our data. Variant chr19-15187163-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.69 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1741/152320) while in subpopulation AFR AF = 0.0388 (1612/41576). AF 95% confidence interval is 0.0372. There are 24 homozygotes in GnomAd4. There are 816 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000435.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.1782C>T	p.Gly594Gly	synonymous	Exon 11 of 33	NP_000426.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.1782C>T	p.Gly594Gly	synonymous	Exon 11 of 33	ENSP00000263388.1
	NOTCH3	ENST00000601011.1	TSL:5	c.1779C>T	p.Gly593Gly	synonymous	Exon 11 of 23	ENSP00000473138.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1735

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00304

AC:

763

AN:

250720

AF XY:

0.00217

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00126

AC:

1842

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

782

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0416

AC:

1392

AN:

33480

American (AMR)

AF:

0.00206

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000139

AC:

155

AN:

1111992

Other (OTH)

AF:

0.00290

AC:

175

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0114

AC:

1741

AN:

152320

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

816

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0388

AC:

1612

AN:

41576

American (AMR)

AF:

0.00523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68020

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00362

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy

Benign:1

Nov 28, 2023

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Dec 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

-1.7

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over