rs80340744

chr9-136506850-G-Achr9-136506850-G-Cchr9-136506850-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.3767C>T(p.Pro1256Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,612,068 control chromosomes in the GnomAD database, including 19 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1256P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (6 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 5.64

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=0.011899173).
• BP6: Variant 9-136506850-G-A is Benign according to our data. Variant chr9-136506850-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00603 (918/152326) while in subpopulation AFR AF= 0.0208 (864/41568). AF 95% confidence interval is 0.0196. There are 13 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 918 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.3767C>T	p.Pro1256Leu	missense_variant	23/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.3044C>T	p.Pro1015Leu	missense_variant	20/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.3767C>T	p.Pro1256Leu	missense_variant	23/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152208 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00151 AC: 369 AN: 244062 Hom.: 3 AF XY: 0.00112 AC XY: 150 AN XY: 133388

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.000906

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000625 AC: 912 AN: 1459742 Hom.: 6 Cov.: 34 AF XY: 0.000534 AC XY: 388 AN XY: 726098

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00603 AC: 918 AN: 152326 Hom.: 13 Cov.: 33 AF XY: 0.00567 AC XY: 422 AN XY: 74484

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00162 Hom.: 1

Bravo AF: 0.00713

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0190 AC: 79

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00192 AC: 231

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adams-Oliver syndrome 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

NOTCH1: PP2, BP4, BS1, BS2 -

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	0.049
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.087
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.19
Sift	Benign	0.56	T
Sift4G	Benign	0.34	T
Polyphen		0.20	B
Vest4		0.80
MVP		0.55
MPC		0.50
ClinPred		0.036	T
GERP RS		4.3
Varity_R		0.19

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: rs80340744; hg19: chr9-139401302; COSMIC: COSV53085728; COSMIC: COSV53085728;