9-136496759-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_017617.5(NOTCH1):c.6980G>A(p.Arg2327Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000213 in 1,612,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2327W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 4.87

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.02677077).
• BP6: Variant 9-136496759-C-T is Benign according to our data. Variant chr9-136496759-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134956.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.6980G>A	p.Arg2327Gln	missense_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.6257G>A	p.Arg2086Gln	missense_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.6980G>A	p.Arg2327Gln	missense_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000206 AC: 51 AN: 247288 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134920

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1460500 Hom.: 1 Cov.: 31 AF XY: 0.000156 AC XY: 113 AN XY: 726550

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000765 AC XY: 57 AN XY: 74492

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.000937

ESP6500AA AF: 0.000989 AC: 4

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000224 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2016	The c.6980G>A (p.R2327Q) alteration is located in exon 34 (coding exon 34) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 6980, causing the arginine (R) at amino acid position 2327 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

NOTCH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2023

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

Adams-Oliver syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.073
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Polyphen		0.96	D
Vest4		0.36
MVP		0.70
MPC		0.94
ClinPred		0.026	T
GERP RS		4.5
Varity_R		0.13

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: rs202065858; hg19: chr9-139391211;