19-15185016-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000435.3(NOTCH3):c.2300G>A(p.Arg767His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,485,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R767C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.527

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: 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004593849).

BP6

Variant 19-15185016-C-T is Benign according to our data. Variant chr19-15185016-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00198 (301/152128) while in subpopulation AFR AF = 0.00665 (276/41512). AF 95% confidence interval is 0.006. There are 1 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2300G>A	p.Arg767His	missense	Exon 15 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.2300G>A	p.Arg767His	missense	Exon 15 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.2435G>A	p.Arg812His	missense	Exon 16 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.2279G>A	p.Arg760His	missense	Exon 15 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000591

AC:

AN:

128500

AF XY:

0.000419

show subpopulations

Gnomad AFR exome

AF:

0.00909

Gnomad AMR exome

AF:

0.000311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

272

AN:

1332952

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

105

AN XY:

653618

show subpopulations

African (AFR)

AF:

0.00705

AC:

215

AN:

30508

American (AMR)

AF:

0.000328

AC:

AN:

33516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22934

East Asian (EAS)

AF:

0.00

AC:

AN:

35164

South Asian (SAS)

AF:

0.0000406

AC:

AN:

73880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47574

Middle Eastern (MID)

AF:

0.000969

AC:

AN:

5162

European-Non Finnish (NFE)

AF:

0.00000972

AC:

AN:

1028804

Other (OTH)

AF:

0.000505

AC:

AN:

55410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152128

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00665

AC:

276

AN:

41512

American (AMR)

AF:

0.00138

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67978

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000461

Hom.:

Bravo

AF:

0.00216

ESP6500AA

AF:

0.00639

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000479

AC:

Asia WGS

AF:

0.00115

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 (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

Benign

0.075

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.16

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

PhyloP100

-0.53

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.54

REVEL

Benign

0.099

Sift

Benign

0.54

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.041

MVP

0.60

MPC

0.52

ClinPred

0.013

GERP RS

1.1

Varity_R

0.017

gMVP

0.27

Mutation Taster

=78/22

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

Computational scores

Splicing

Publications

Other links and lift over