rs3812596

Variant names:

Variant summary

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

The NM_017617.5(NOTCH1):c.6648G>A(p.Pro2216Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,609,458 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 153 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.70

Publications

10 publications found

Variant links:

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
Adams-Oliver syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
NOTCH1-related AOS spectrum disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
aortic valve disease 1
Inheritance: AD Classification: STRONG Submitted by: G2P
connective tissue disorder
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leukodystrophy
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
familial bicuspid aortic valve
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NOTCH1 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=-0.7).

BP6

Variant 9-136497091-C-T is Benign according to our data. Variant chr9-136497091-C-T is described in ClinVar as Benign. ClinVar VariationId is 287652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017617.5. 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
	NOTCH1	NM_017617.5	MANE Select	c.6648G>A	p.Pro2216Pro	synonymous	Exon 34 of 34	NP_060087.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH1	ENST00000651671.1	MANE Select	c.6648G>A	p.Pro2216Pro	synonymous	Exon 34 of 34	ENSP00000498587.1	P46531
NOTCH1	ENST00000927794.1		c.6537G>A	p.Pro2179Pro	synonymous	Exon 34 of 34	ENSP00000597853.1
NOTCH1	ENST00000680133.1		c.6534G>A	p.Pro2178Pro	synonymous	Exon 33 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1601

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0567

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.0121

AC:

2962

AN:

244490

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.000406

Gnomad EAS exome

AF:

0.0541

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.00436

AC:

6349

AN:

1457174

Hom.:

153

Cov.:

AF XY:

0.00430

AC XY:

3117

AN XY:

724348

show subpopulations

African (AFR)

AF:

0.0160

AC:

534

AN:

33424

American (AMR)

AF:

0.0386

AC:

1722

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

26058

East Asian (EAS)

AF:

0.0638

AC:

2526

AN:

39598

South Asian (SAS)

AF:

0.00420

AC:

362

AN:

86160

European-Finnish (FIN)

AF:

0.00177

AC:

AN:

51486

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000725

AC:

805

AN:

1109858

Other (OTH)

AF:

0.00474

AC:

285

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

470

940

1409

1879

2349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.0106

AC:

1613

AN:

152284

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

862

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0170

AC:

706

AN:

41566

American (AMR)

AF:

0.0304

AC:

466

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0568

AC:

294

AN:

5176

South Asian (SAS)

AF:

0.00664

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68010

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00636

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Adams-Oliver syndrome 5 (2)

Familial thoracic aortic aneurysm and aortic dissection (2)

Aortic valve disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.26

(source)

DANN

Benign

0.84

PhyloP100

-2.7

Mutation Taster

=79/21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over