rs16980398

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000435.3(NOTCH3):c.5526T>C(p.Ala1842Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,614,030 control chromosomes in the GnomAD database, including 5,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 3033 hom., cov: 32)

Exomes 𝑓: 0.018 ( 2817 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.674

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 19-15165928-A-G is Benign according to our data. Variant chr19-15165928-A-G is described in ClinVar as Benign. ClinVar VariationId is 256144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.674 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.5526T>C	p.Ala1842Ala	synonymous_variant	Exon 30 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.5370T>C	p.Ala1790Ala	synonymous_variant	Exon 29 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOTCH3	ENST00000263388.7 link	c.5526T>C	p.Ala1842Ala	synonymous_variant	Exon 30 of 33	1	NM_000435.3	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000597756.1 link	c.39T>C	p.Ala13Ala	synonymous_variant	Exon 1 of 3	2		ENSP00000468879.1	M0QX38
NOTCH3	ENST00000595514.1 link	n.227-413T>C		intron_variant	Intron 2 of 4	3		ENSP00000470661.1	M0QZN3

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17321

AN:

152036

Hom.:

3018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0415

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00704

Gnomad OTH

AF:

0.0818

GnomAD2 exomes

AF:

0.0352

AC:

8840

AN:

251236

AF XY:

0.0288

show subpopulations

Gnomad AFR exome

AF:

0.388

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0267

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00669

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0176

AC:

25702

AN:

1461876

Hom.:

2817

Cov.:

AF XY:

0.0166

AC XY:

12067

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.390

AC:

13041

AN:

33480

American (AMR)

AF:

0.0221

AC:

990

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0261

AC:

683

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0220

AC:

1901

AN:

86258

European-Finnish (FIN)

AF:

0.00223

AC:

119

AN:

53418

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.00618

AC:

6872

AN:

1112000

Other (OTH)

AF:

0.0320

AC:

1930

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1387

2774

4160

5547

6934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.114

AC:

17368

AN:

152154

Hom.:

3033

Cov.:

AF XY:

0.110

AC XY:

8153

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.380

AC:

15761

AN:

41458

American (AMR)

AF:

0.0414

AC:

633

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.0186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00704

AC:

479

AN:

68018

Other (OTH)

AF:

0.0810

AC:

171

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

563

1126

1690

2253

2816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.0473

Hom.:

3276

Bravo

AF:

0.129

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00652

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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 12, 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

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.7

(source)

DANN

Benign

0.54

PhyloP100

-0.67

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(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