rs141320511

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.4552C>A(p.Leu1518Met) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,585,906 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 19 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.81

Publications

25 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011193216).

BP6

Variant 19-15174252-G-T is Benign according to our data. Variant chr19-15174252-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00248 (378/152366) while in subpopulation EAS AF = 0.00829 (43/5184). AF 95% confidence interval is 0.00633. There are 1 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.4552C>A	p.Leu1518Met	missense	Exon 25 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.4552C>A	p.Leu1518Met	missense	Exon 25 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.4687C>A	p.Leu1563Met	missense	Exon 26 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.4375C>A	p.Leu1459Met	missense	Exon 24 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00371

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00828

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00466

AC:

910

AN:

195106

AF XY:

0.00401

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.00463

Gnomad EAS exome

AF:

0.00687

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000482

Gnomad OTH exome

AF:

0.00467

GnomAD4 exome

AF:

0.00147

AC:

2112

AN:

1433540

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1075

AN XY:

711922

show subpopulations

African (AFR)

AF:

0.00429

AC:

141

AN:

32838

American (AMR)

AF:

0.0163

AC:

661

AN:

40528

Ashkenazi Jewish (ASJ)

AF:

0.00354

AC:

AN:

25700

East Asian (EAS)

AF:

0.00951

AC:

362

AN:

38082

South Asian (SAS)

AF:

0.00449

AC:

377

AN:

84014

European-Finnish (FIN)

AF:

0.0000215

AC:

AN:

46586

Middle Eastern (MID)

AF:

0.00359

AC:

AN:

5292

European-Non Finnish (NFE)

AF:

0.000219

AC:

241

AN:

1101160

Other (OTH)

AF:

0.00369

AC:

219

AN:

59340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

134

268

403

537

671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00248

AC:

378

AN:

152366

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00373

AC:

155

AN:

41586

American (AMR)

AF:

0.00660

AC:

101

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00829

AC:

AN:

5184

South Asian (SAS)

AF:

0.00579

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

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:

0.00187

Hom.:

Bravo

AF:

0.00346

ESP6500AA

AF:

0.00301

AC:

ESP6500EA

AF:

0.000591

AC:

ExAC

AF:

0.00317

AC:

375

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)

not specified (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.8

PhyloP100

4.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.28

MVP

0.85

MPC

2.6

ClinPred

0.016

GERP RS

4.8

Varity_R

0.69

gMVP

0.54

Mutation Taster

=41/59

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over