rs767728582

chr9-136496516-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_017617.5(NOTCH1):c.7223T>C(p.Leu2408Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000542 in 1,604,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2408V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.91

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.08566216).
• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.7223T>C	p.Leu2408Pro	missense_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.6500T>C	p.Leu2167Pro	missense_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.7223T>C	p.Leu2408Pro	missense_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000958 AC: 23 AN: 239974 Hom.: 0 AF XY: 0.0000609 AC XY: 8 AN XY: 131450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000609

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: 0.00000902

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000303 AC: 44 AN: 1452084 Hom.: 0 Cov.: 31 AF XY: 0.0000263 AC XY: 19 AN XY: 722768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.000215

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 2023	The c.7223T>C (p.L2408P) alteration is located in exon 34 (coding exon 34) of the NOTCH1 gene. This alteration results from a T to C substitution at nucleotide position 7223, causing the leucine (L) at amino acid position 2408 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2020

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 477969; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Adams-Oliver syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.25	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.32
Sift	Benign	0.31	T
Sift4G	Benign	0.22	T
Polyphen		0.88	P
Vest4		0.13
MVP		0.88
MPC		0.57
ClinPred		0.091	T
GERP RS		5.2
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: rs767728582; hg19: chr9-139390968;