rs61749020

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1140T>C(p.Pro380Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,614,002 control chromosomes in the GnomAD database, including 862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 85 hom., cov: 32)

Exomes 𝑓: 0.029 ( 777 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.18

Publications

10 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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=-0.82).

BP6

Variant 19-15189325-A-G is Benign according to our data. Variant chr19-15189325-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.18 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.1140T>C	p.Pro380Pro	synonymous	Exon 7 of 33	NP_000426.2	Q9UM47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.1140T>C	p.Pro380Pro	synonymous	Exon 7 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.1140T>C	p.Pro380Pro	synonymous	Exon 7 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.1119T>C	p.Pro373Pro	synonymous	Exon 7 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4065

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0468

GnomAD2 exomes

AF:

0.0265

AC:

6658

AN:

251294

AF XY:

0.0272

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00751

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0287

AC:

41895

AN:

1461740

Hom.:

777

Cov.:

AF XY:

0.0288

AC XY:

20950

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0191

AC:

638

AN:

33480

American (AMR)

AF:

0.0237

AC:

1059

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2976

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0171

AC:

1478

AN:

86258

European-Finnish (FIN)

AF:

0.00880

AC:

469

AN:

53274

Middle Eastern (MID)

AF:

0.0562

AC:

324

AN:

5768

European-Non Finnish (NFE)

AF:

0.0296

AC:

32939

AN:

1112004

Other (OTH)

AF:

0.0332

AC:

2008

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2751

5502

8252

11003

13754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1246

2492

3738

4984

6230

<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:

0.0267

AC:

4064

AN:

152262

Hom.:

Cov.:

AF XY:

0.0260

AC XY:

1933

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0185

AC:

770

AN:

41542

American (AMR)

AF:

0.0362

AC:

553

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

373

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0170

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0298

AC:

2029

AN:

68014

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0300

Hom.:

Bravo

AF:

0.0283

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0364

EpiControl

AF:

0.0396

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

(source)

DANN

Benign

0.33

PhyloP100

-1.2

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over