9-136504868-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_017617.5(NOTCH1):c.4823G>A(p.Arg1608His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,583,276 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts 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. R1608C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (110 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.52

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=0.006784916).
• BP6: Variant 9-136504868-C-T is Benign according to our data. Variant chr9-136504868-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136504868-C-T is described in Lovd as [Likely_benign]. Variant chr9-136504868-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.4823G>A	p.Arg1608His	missense_variant	26/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.4100G>A	p.Arg1367His	missense_variant	23/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.4823G>A	p.Arg1608His	missense_variant	26/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152210 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0349

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0105 AC: 2085 AN: 198036 Hom.: 98 AF XY: 0.00805 AC XY: 862 AN XY: 107136

Gnomad AFR exome AF: 0.000963

Gnomad AMR exome AF: 0.0684

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000780

Gnomad FIN exome AF: 0.000821

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.00787

GnomAD4 exome AF: 0.00210 AC: 2999 AN: 1430948 Hom.: 110 Cov.: 33 AF XY: 0.00181 AC XY: 1285 AN XY: 708870

Gnomad4 AFR exome AF: 0.000513

Gnomad4 AMR exome AF: 0.0628

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.000156

Gnomad4 SAS exome AF: 0.0000853

Gnomad4 FIN exome AF: 0.000705

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152328 Hom.: 20 Cov.: 33 AF XY: 0.00460 AC XY: 343 AN XY: 74486

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00238 Hom.: 14

Bravo AF: 0.00667

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000927 AC: 4

ESP6500EA AF: 0.000588 AC: 5

ExAC AF: 0.00647 AC: 774

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 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. -

Adams-Oliver syndrome 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 12, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	0.080
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.74	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.64
Sift	Benign	0.060	T
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.77
MPC		1.9
ClinPred		0.014	T
GERP RS		2.2
Varity_R		0.14

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: rs76371972; hg19: chr9-139399320;