rs191892426

chr9-136514500-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017617.5(NOTCH1):c.2207+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,562,560 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (32 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.109

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-136514500-C-T is Benign according to our data. Variant chr9-136514500-C-T is described in ClinVar as [Benign]. Clinvar id is 241123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136514500-C-T is described in Lovd as [Benign]. Variant chr9-136514500-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 517 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.2207+10G>A		intron_variant		ENST00000651671.1
LOC124902310	XR_007061865.1	n.507+4521C>T		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.1484+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.2207+10G>A		intron_variant			NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 517 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00344 AC: 590 AN: 171278 Hom.: 2 AF XY: 0.00340 AC XY: 313 AN XY: 91994

Gnomad AFR exome AF: 0.000599

Gnomad AMR exome AF: 0.00404

Gnomad ASJ exome AF: 0.00173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.000688

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00558 AC: 7875 AN: 1410232 Hom.: 32 Cov.: 33 AF XY: 0.00542 AC XY: 3780 AN XY: 697092

Gnomad4 AFR exome AF: 0.000887

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.00202

Gnomad4 EAS exome AF: 0.0000802

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00652

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00316 AC XY: 235 AN XY: 74480

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00380 Hom.: 1

Bravo AF: 0.00368

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	NOTCH1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:2

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	Jul 21, 2023	- -

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 27, 2017

- -

Aortic valve disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.3
Dann	Benign	0.29

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

Other links and lift over

dbSNP: rs191892426; hg19: chr9-139408952; COSMIC: COSV104540440; COSMIC: COSV104540440;