rs3124603

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_StrongBA1

The NM_017617.5(NOTCH1):c.1670-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,532,674 control chromosomes in the GnomAD database, including 124,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18484 hom., cov: 33)

Exomes 𝑓: 0.38 ( 106398 hom. )

Consequence

NOTCH1
NM_017617.5 intron

Scores

Splicing: ADA: 0.00001907

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.29

Publications

27 publications found

Variant links:

COSMIC-nc: COSV53028879

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:

LOC124902310 (HGNC:):

LOC124902310 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 (BayesDel_noAF=-0.87).

BP6

Variant 9-136515725-T-C is Benign according to our data. Variant chr9-136515725-T-C is described in ClinVar as Benign. ClinVar VariationId is 288086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 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.1670-9A>G		intron	N/A	NP_060087.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOTCH1	ENST00000651671.1	MANE Select	c.1670-9A>G	intron	N/A	ENSP00000498587.1	P46531
NOTCH1	ENST00000927794.1		c.1670-120A>G	intron	N/A	ENSP00000597853.1
NOTCH1	ENST00000680133.1		c.1556-9A>G	intron	N/A	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71551

AN:

151898

Hom.:

18460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.639

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.495

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.854

Gnomad SAS

AF:

0.418

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.462

AC:

64152

AN:

138994

AF XY:

0.450

show subpopulations

Gnomad AFR exome

AF:

0.645

Gnomad AMR exome

AF:

0.586

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.850

Gnomad FIN exome

AF:

0.478

Gnomad NFE exome

AF:

0.344

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.377

AC:

520916

AN:

1380658

Hom.:

106398

Cov.:

AF XY:

0.377

AC XY:

257088

AN XY:

681094

show subpopulations

African (AFR)

AF:

0.648

AC:

20397

AN:

31500

American (AMR)

AF:

0.570

AC:

20345

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

7873

AN:

25116

East Asian (EAS)

AF:

0.873

AC:

31176

AN:

35726

South Asian (SAS)

AF:

0.422

AC:

33427

AN:

79264

European-Finnish (FIN)

AF:

0.474

AC:

16468

AN:

34706

Middle Eastern (MID)

AF:

0.356

AC:

1456

AN:

4088

European-Non Finnish (NFE)

AF:

0.340

AC:

366380

AN:

1076938

Other (OTH)

AF:

0.406

AC:

23394

AN:

57616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

18617

37235

55852

74470

93087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12172

24344

36516

48688

60860

<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:

0.471

AC:

71626

AN:

152016

Hom.:

18484

Cov.:

AF XY:

0.478

AC XY:

35524

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.638

AC:

26456

AN:

41458

American (AMR)

AF:

0.495

AC:

7566

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1084

AN:

3470

East Asian (EAS)

AF:

0.856

AC:

4414

AN:

5158

South Asian (SAS)

AF:

0.418

AC:

2012

AN:

4818

European-Finnish (FIN)

AF:

0.490

AC:

5191

AN:

10588

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.347

AC:

23570

AN:

67914

Other (OTH)

AF:

0.421

AC:

888

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1859

3717

5576

7434

9293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

0.405

Hom.:

22228

Bravo

AF:

0.484

Asia WGS

AF:

0.632

AC:

2197

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Adams-Oliver syndrome 5 (2)

Aortic valve disease 1 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.4

(source)

DANN

Benign

0.23

PhyloP100

-1.3

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.010

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