rs201163739

Positions:

• chr9-136509030-G-A
• chr9-136509030-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_017617.5(NOTCH1):​c.3011C>T​(p.Ser1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,563,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S1004A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 6.53

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=0.27358446).
• BP6: Variant 9-136509030-G-A is Benign according to our data. Variant chr9-136509030-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 561320.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}. Variant chr9-136509030-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.3011C>T	p.Ser1004Leu	missense_variant	19/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.2288C>T	p.Ser763Leu	missense_variant	16/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.3011C>T	p.Ser1004Leu	missense_variant	19/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152260 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 30 AN: 173498 Hom.: 0 AF XY: 0.000150 AC XY: 14 AN XY: 93168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000418

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.000112 AC: 158 AN: 1411060 Hom.: 0 Cov.: 35 AF XY: 0.000110 AC XY: 77 AN XY: 697274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.000948

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152260 Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000777 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Has not been published in association with cardiovascular disease; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27870570) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 23, 2022	PP2 -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2022	The p.S1004L variant (also known as c.3011C>T), located in coding exon 19 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 3011. The serine at codon 1004 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 25, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 14, 2023

Variant summary: NOTCH1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR008297) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 173498 control chromosomes. The observed variant frequency is approximately 280 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3011C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

NOTCH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2022

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 06, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.85	P
Vest4		0.45
MVP		0.56
MPC		0.60
ClinPred		0.41	T
GERP RS		4.9
Varity_R		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201163739; hg19: chr9-139403482; COSMIC: COSV104586547; COSMIC: COSV104586547;