9-136515687-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017617.5(NOTCH1):c.1699A>G(p.Ile567Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,552,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 2.66

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 links:

LOC124902310 (HGNC:):

LOC124902310 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011598438).

BP6

Variant 9-136515687-T-C is Benign according to our data. Variant chr9-136515687-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134907.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000164 (25/152294) while in subpopulation EAS AF= 0.00251 (13/5178). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.1699A>G	p.Ile567Val	missense_variant	Exon 11 of 34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.976A>G	p.Ile326Val	missense_variant	Exon 8 of 31		XP_011517019.2
LOC124902310	XR_007061865.1 link	n.507+5708T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.1699A>G	p.Ile567Val	missense_variant	Exon 11 of 34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000364

AC:

AN:

156768

Hom.:

AF XY:

0.000389

AC XY:

AN XY:

84750

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00326

Gnomad SAS exome

AF:

0.000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000154

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000964

AC:

135

AN:

1400352

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

692620

show subpopulations

Gnomad4 AFR exome

AF:

0.0000624

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00126

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000101

Gnomad4 OTH exome

AF:

0.000532

GnomAD4 genome

AF:

0.000164

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Feb 01, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2024

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. -

not provided

Benign:2

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH1: PP2, BS1, BS2 -

Mar 27, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Nov 26, 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;C4014970:Adams-Oliver syndrome 5

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adams-Oliver syndrome 5

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.068

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.69

REVEL

Uncertain

0.37

Sift

Benign

0.063

Sift4G

Benign

0.14

Polyphen

0.019

Vest4

0.41

MVP

0.75

MPC

0.32

ClinPred

0.026

GERP RS

5.0

Varity_R

0.058

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over