9-136506788-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP6_ModerateBS2

The NM_017617.5(NOTCH1):c.3829G>A(p.Asp1277Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,611,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. D1277D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.71

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 -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, NOTCH1

BP6

Variant 9-136506788-C-T is Benign according to our data. Variant chr9-136506788-C-T is described in ClinVar as [Benign]. Clinvar id is 544185.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.3829G>A	p.Asp1277Asn	missense_variant	23/34	ENST00000651671.1
NOTCH1	XM_011518717.3 linkuse as main transcript	c.3106G>A	p.Asp1036Asn	missense_variant	20/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.3829G>A	p.Asp1277Asn	missense_variant	23/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000206

AC:

AN:

242610

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

132464

show subpopulations

Gnomad AFR exome

AF:

0.0000678

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000170

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1458680

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725532

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.40

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.040

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.31

Sift

Benign

0.20

Sift4G

Benign

1.0

Polyphen

1.0

Vest4

0.70

MutPred

0.44

Loss of phosphorylation at T1281 (P = 0.2594);

MVP

0.59

MPC

1.2

ClinPred

0.34

GERP RS

5.2

Varity_R

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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