9-136496450-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017617.5(NOTCH1):c.7289G>C(p.Gly2430Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,600,282 control chromosomes in the GnomAD database, including 4 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 (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 4 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.64

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006912142).

BP6

Variant 9-136496450-C-G is Benign according to our data. Variant chr9-136496450-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 264535.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 = 0.00184 (280/152364) while in subpopulation AFR AF = 0.00656 (273/41588). AF 95% confidence interval is 0.00592. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 280 AD gene.

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.7289G>C	p.Gly2430Ala	missense	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.7289G>C	p.Gly2430Ala	missense	Exon 34 of 34	ENSP00000498587.1	P46531
NOTCH1	ENST00000927794.1		c.7178G>C	p.Gly2393Ala	missense	Exon 34 of 34	ENSP00000597853.1
NOTCH1	ENST00000680133.1		c.7175G>C	p.Gly2392Ala	missense	Exon 33 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00656

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000409

AC:

AN:

234508

AF XY:

0.000357

show subpopulations

Gnomad AFR exome

AF:

0.00599

Gnomad AMR exome

AF:

0.000175

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:

0.000170

GnomAD4 exome

AF:

0.000188

AC:

272

AN:

1447918

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

123

AN XY:

720748

show subpopulations

African (AFR)

AF:

0.00702

AC:

235

AN:

33472

American (AMR)

AF:

0.000201

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39858

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111820

Other (OTH)

AF:

0.000265

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

114

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:

0.00184

AC:

280

AN:

152364

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00656

AC:

273

AN:

41588

American (AMR)

AF:

0.000392

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000721

Hom.:

Bravo

AF:

0.00207

ESP6500AA

AF:

0.00403

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000407

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adams-Oliver syndrome 5 (2)

not specified (2)

Aortic valve disease 1 (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.33

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.67

M_CAP

Benign

0.072

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.9

PhyloP100

1.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Benign

0.22

Sift

Benign

0.099

Sift4G

Benign

0.13

Polyphen

0.56

Vest4

0.070

MVP

0.81

MPC

0.38

ClinPred

0.020

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

Mutation Taster

=66/34

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

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