9-136519469-T-C

Position:

chr9-136519469-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_017617.5(NOTCH1):c.839A>G(p.Asn280Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,612,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 34)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 6.13

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 -8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BP6

Variant 9-136519469-T-C is Benign according to our data. Variant chr9-136519469-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409078.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152172) while in subpopulation NFE AF= 0.000294 (20/68022). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.839A>G	p.Asn280Ser	missense_variant	5/34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.116A>G	p.Asn39Ser	missense_variant	2/31		XP_011517019.2
LOC124902310	XR_007061865.1 link	n.508-3849T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.839A>G	p.Asn280Ser	missense_variant	5/34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

246648

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000986

AC:

144

AN:

1460162

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

726370

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

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:

0.000121

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000911

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2022

The p.N280S variant (also known as c.839A>G), located in coding exon 5 of the NOTCH1 gene, results from an A to G substitution at nucleotide position 839. The asparagine at codon 280 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in congenital heart disease and sudden infant death cohorts (Kerstjens-Frederikse WS et al. Genet Med, 2016 09;18:914-23; Neubauer J et al. Eur J Hum Genet, 2017 04;25:404-409). This amino acid position is highly conserved in available 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. -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 06, 2023

Reported in a family with aortic coarctation and thickened aortic valve, however complete clinical and segregation information was not provided (PMID: 26820064); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26820064) -

Aortic valve disease 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 15, 2023

Variant summary: NOTCH1 c.839A>G (p.Asn280Ser) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 246648 control chromosomes. The observed variant frequency is approximately 168.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is benign. c.839A>G has been reported in the literature in individuals affected with coarctation of the aorta (Kerstjens-Frederikse_2016), SIDS (Neubauer_2017), and sporadic bicuspid aortic valve (Debiec_2022), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Adams-Oliver Syndrome 5. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35288444, 26820064, 28074886). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four classified the variant as VUS while one classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.0094

MutationAssessor

Benign

-0.28

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.52

Sift

Benign

0.15

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.65

MVP

0.85

MPC

1.1

ClinPred

0.28

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

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