9-136515524-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_017617.5(NOTCH1):c.1862G>A(p.Arg621His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,611,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R621L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 2.47

Publications

21 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: Illumina, Orphanet
Adams-Oliver syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
aortic valve disease 1
Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
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
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12021786).

BP6

Variant 9-136515524-C-T is Benign according to our data. Variant chr9-136515524-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000906 (138/152304) while in subpopulation NFE AF = 0.00157 (107/68014). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NOTCH1	NM_017617.5 link	c.1862G>A	p.Arg621His	missense_variant	Exon 11 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 link	c.1139G>A	p.Arg380His	missense_variant	Exon 8 of 31		XP_011517019.2
LOC124902310	XR_007061865.1 link	n.507+5545C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.1862G>A	p.Arg621His	missense_variant	Exon 11 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00104

AC:

254

AN:

245308

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00191

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.000636

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.00120

AC:

1748

AN:

1459622

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

870

AN XY:

726184

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33470

American (AMR)

AF:

0.000246

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.000232

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000777

AC:

AN:

51474

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00134

AC:

1491

AN:

1111828

Other (OTH)

AF:

0.00167

AC:

101

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

113

225

338

450

563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000906

AC:

138

AN:

152304

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41568

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68014

Other (OTH)

AF:

0.000945

AC:

AN:

2116

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

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:

0.00160

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000929

AC:

ESP6500EA

AF:

0.00141

AC:

ExAC

AF:

0.00115

AC:

139

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 28387797) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOTCH1: BS1, BS2 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Feb 01, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 14, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adams-Oliver syndrome 5

Benign:2

Mar 15, 2022

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic valve disease 1

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.32

PhyloP100

2.5

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.55

Sift

Benign

0.14

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.60

MVP

0.78

MPC

1.3

ClinPred

0.043

GERP RS

5.2

Varity_R

0.15

Mutation Taster

=74/26

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over