rs61751491

Positions:

chr9-136497012-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_017617.5(NOTCH1):c.6727G>A(p.Gly2243Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,609,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.10217139).

BP6

Variant 9-136497012-C-T is Benign according to our data. Variant chr9-136497012-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 519561.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.6727G>A	p.Gly2243Ser	missense_variant	34/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 linkuse as main transcript	c.6004G>A	p.Gly2002Ser	missense_variant	31/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.6727G>A	p.Gly2243Ser	missense_variant	34/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000287

AC:

AN:

243582

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133384

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000455

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000343

AC:

AN:

1457606

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000498

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 17, 2024	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2023

The p.G2243S variant (also known as c.6727G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6727. The glycine at codon 2243 is replaced by serine, an amino acid with similar properties. This variant was detected in a pediatric patient with T-cell acute lymphoblastic leukemia where NOTCH1 was only partially sequenced and clinical information was not available (Kraszewska MD et al, Blood Cells Mol. Dis. 2013 Jan; 50(1):33-8). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Adams-Oliver syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.28

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

M_CAP

Benign

0.052

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.27

MutationTaster

Benign

0.98

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.52

REVEL

Benign

0.17

Sift

Benign

0.39

Sift4G

Benign

0.40

Polyphen

0.043

Vest4

0.039

MVP

0.62

MPC

0.36

ClinPred

0.030

GERP RS

4.4

Varity_R

0.060

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