chr9-136523737-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_017617.5(NOTCH1):c.383G>T(p.Arg128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,456,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.38

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: 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 9-136523737-C-A is Benign according to our data. Variant chr9-136523737-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2037213.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.383G>T	p.Arg128Leu	missense_variant	Exon 3 of 34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.20-4172G>T		intron_variant	Intron 1 of 30		XP_011517019.2
LOC124902310	XR_007061865.1 link	n.623+304C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.383G>T	p.Arg128Leu	missense_variant	Exon 3 of 34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000837

AC:

AN:

239062

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000591

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:

0.00000481

AC:

AN:

1456730

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.0000902

AC:

AN:

44370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.00

AC:

AN:

85610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4852

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111002

Other (OTH)

AF:

0.00

AC:

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5

Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.29

PhyloP100

1.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.22

Sift

Benign

0.33

Sift4G

Benign

0.31

Polyphen

0.0080

Vest4

0.24

MutPred

0.58

Gain of catalytic residue at R128 (P = 0.0503);

MVP

0.67

MPC

0.50

ClinPred

0.18

GERP RS

2.3

Varity_R

0.12

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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chr9-136523737-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over