Genetic Variant NM_000435.3:c.4556T>C (chr19-15174248-A-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000435.3(NOTCH3):c.4556T>C(p.Leu1519Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 9.11

Publications

17 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 19-15174248-A-G is Pathogenic according to our data. Variant chr19-15174248-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55850.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.4556T>C	p.Leu1519Pro	missense_variant	Exon 25 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.4400T>C	p.Leu1467Pro	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.4556T>C	p.Leu1519Pro	missense_variant	Exon 25 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1435718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713186

African (AFR)

AF:

0.00

AC:

AN:

32926

American (AMR)

AF:

0.00

AC:

AN:

40998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

38360

South Asian (SAS)

AF:

0.00

AC:

AN:

84262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101968

Other (OTH)

AF:

0.00

AC:

AN:

59388

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Myofibromatosis, infantile, 2

Pathogenic:1

Jun 06, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Myofibromatosis, infantile, 1

Other:1

Center for Applied Genomics, Children's Hospital of Philadelphia

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

PhyloP100

9.1

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.98

Vest4

0.86

MutPred

0.79

Gain of glycosylation at L1519 (P = 0.0169);

MVP

0.97

MPC

3.4

ClinPred

0.99

GERP RS

4.8

Varity_R

0.97

gMVP

0.95

Mutation Taster

=11/89

disease causing (ClinVar)

(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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over