rs114832250

chr9-136544100-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):c.64C>T(p.Pro22Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,571,134 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (5 hom.)
• Consequence: NOTCH1 NM_017617.5 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.59

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060311854).
• BP6: Variant 9-136544100-G-A is Benign according to our data. Variant chr9-136544100-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136544100-G-A is described in Lovd as [Benign]. Variant chr9-136544100-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (842/152326) while in subpopulation AFR AF= 0.0178 (738/41564). AF 95% confidence interval is 0.0167. There are 2 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.64C>T	p.Pro22Ser	missense_variant, splice_region_variant	2/34	ENST00000651671.1
NOTCH1	XM_011518717.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.64C>T	p.Pro22Ser	missense_variant, splice_region_variant	2/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00164 AC: 298 AN: 181272 Hom.: 1 AF XY: 0.00137 AC XY: 133 AN XY: 97430

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.000451

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000123

Gnomad FIN exome AF: 0.000183

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.000736 AC: 1044 AN: 1418808 Hom.: 5 Cov.: 31 AF XY: 0.000697 AC XY: 489 AN XY: 701926

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000550

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000866

Gnomad4 FIN exome AF: 0.0000808

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00585 AC XY: 436 AN XY: 74492

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00259 Hom.: 4

Bravo AF: 0.00623

ESP6500AA AF: 0.0115 AC: 48

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00142 AC: 167

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2015	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. -

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

NOTCH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	19
Dann	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.11
Sift	Benign	0.073	T
Sift4G	Benign	0.43	T
Polyphen		0.046	B
Vest4		0.14
MVP		0.54
MPC		0.39
ClinPred		0.0038	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031

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: rs114832250; hg19: chr9-139438552; COSMIC: COSV53038631; COSMIC: COSV53038631;