9-136510809-C-T

Position:

chr9-136510809-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017617.5(NOTCH1):c.2588-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,607,682 control chromosomes in the GnomAD database, including 145,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19496 hom., cov: 34)

Exomes 𝑓: 0.40 ( 125963 hom. )

Consequence

NOTCH1
NM_017617.5 splice_region, intron

Scores

Splicing: ADA: 0.00002070

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.276

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 9-136510809-C-T is Benign according to our data. Variant chr9-136510809-C-T is described in ClinVar as [Benign]. Clinvar id is 281108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136510809-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.2588-4G>A	splice_region_variant, intron_variant	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.1865-4G>A	splice_region_variant, intron_variant		XP_011517019.2
LOC124902310	XR_007061864.1 link	n.508-221C>T	intron_variant
LOC124902310	XR_007061865.1 link	n.507+830C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.2588-4G>A		splice_region_variant, intron_variant			NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74146

AN:

151984

Hom.:

19467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.273

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.855

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.465

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.378

Gnomad OTH

AF:

0.477

GnomAD3 exomes

AF:

0.475

AC:

113692

AN:

239218

Hom.:

29819

AF XY:

0.459

AC XY:

60308

AN XY:

131398

show subpopulations

Gnomad AFR exome

AF:

0.658

Gnomad AMR exome

AF:

0.593

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.875

Gnomad SAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.383

Gnomad OTH exome

AF:

0.442

GnomAD4 exome

AF:

0.404

AC:

587941

AN:

1455580

Hom.:

125963

Cov.:

AF XY:

0.402

AC XY:

291086

AN XY:

724460

show subpopulations

Gnomad4 AFR exome

AF:

0.655

Gnomad4 AMR exome

AF:

0.578

Gnomad4 ASJ exome

AF:

0.421

Gnomad4 EAS exome

AF:

0.824

Gnomad4 SAS exome

AF:

0.382

Gnomad4 FIN exome

AF:

0.461

Gnomad4 NFE exome

AF:

0.371

Gnomad4 OTH exome

AF:

0.439

GnomAD4 genome

AF:

0.488

AC:

74242

AN:

152102

Hom.:

19496

Cov.:

AF XY:

0.493

AC XY:

36645

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.646

Gnomad4 AMR

AF:

0.509

Gnomad4 ASJ

AF:

0.412

Gnomad4 EAS

AF:

0.855

Gnomad4 SAS

AF:

0.374

Gnomad4 FIN

AF:

0.465

Gnomad4 NFE

AF:

0.378

Gnomad4 OTH

AF:

0.481

Alfa

AF:

0.417

Hom.:

5150

Bravo

AF:

0.505

Asia WGS

AF:

0.620

AC:

2154

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Aortic valve disease 1

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Adams-Oliver syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

This alteration is classified as 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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.1

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0

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