rs61733294

chr9-136497342-G-Achr9-136497342-G-T

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.6397C>T(p.Pro2133Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00091 in 1,606,230 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 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. P2133T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (10 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.90

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=0.007848561).
• BP6: Variant 9-136497342-G-A is Benign according to our data. Variant chr9-136497342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 264614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136497342-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00494 (752/152362) while in subpopulation AFR AF= 0.017 (705/41592). AF 95% confidence interval is 0.0159. There are 5 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 753 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.6397C>T	p.Pro2133Ser	missense_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.5674C>T	p.Pro1892Ser	missense_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.6397C>T	p.Pro2133Ser	missense_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00114 AC: 272 AN: 238536 Hom.: 5 AF XY: 0.000877 AC XY: 115 AN XY: 131200

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000495

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: 0.0000185

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000488 AC: 710 AN: 1453868 Hom.: 10 Cov.: 39 AF XY: 0.000437 AC XY: 316 AN XY: 723512

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000896

GnomAD4 genome AF: 0.00494 AC: 752 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74508

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000270 Hom.: 1

Bravo AF: 0.00547

ESP6500AA AF: 0.0140 AC: 59

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00136 AC: 163

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Jan 05, 2017	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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

NOTCH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Benign	0.46
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.35
Sift	Benign	0.73	T
Sift4G	Benign	0.44	T
Polyphen		0.13	B
Vest4		0.60
MVP		0.55
MPC		0.38
ClinPred		0.022	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079

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: rs61733294; hg19: chr9-139391794;